review article genetic abnormalities in chronic lymphocytic...

Review ArticleGenetic Abnormalities in Chronic Lymphocytic LeukemiaWhere We Are and Where We Go

Anna Puiggros12 Gonzalo Blanco123 and Blanca Espinet12

1 Laboratori de Citogenetica Molecular Servei de Patologia Hospital del Mar Passeig Marıtim 25-29 08003 Barcelona Spain2 GRETNHE Programa de Recerca en Cancer Institut Hospital del Mar drsquoInvestigacions Mediques Doctor Aiguader 8808003 Barcelona Spain

3 Department of Experimental and Health Sciences Universitat Pompeu Fabra Doctor Aiguader 88 08003 Barcelona Spain

Correspondence should be addressed to Blanca Espinet bespinetparcdesalutmarcat

Received 13 March 2014 Accepted 22 April 2014 Published 22 May 2014

Academic Editor Ana Eugenia Rodrıguez-Vicente

Copyright copy 2014 Anna Puiggros et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Chromosomal abnormalities in chronic lymphocytic leukemia (CLL) are detected in up to 80 of patients Among them deletionsof 11q 13q 17p and trisomy 12 have a known prognostic value and play an important role in CLL pathogenesis and evolutiondetermining patients outcome and therapeutic strategies Standard methods used to identify these genomic aberrations includeboth conventional G-banding cytogenetics (CGC) and fluorescence in situ hybridization (FISH) Although FISH analyses have beenimplemented as the gold standard CGC allows the identification of chromosomal translocations and complex karyotypes the latestassociated with poor outcome Genomic arrays have a higher resolution that allows the detection of cryptic abnormalities althoughthese have not been fully implemented in routine laboratories In the last years next generation sequencing (NGS) methods haveidentified a wide range of gene mutations (eg TP53 NOTCH1 SF3B1 and BIRC3) which have improved our knowledge aboutCLL development allowing us to refine both the prognostic subgroups and better therapeutic strategies Clonal evolution has alsorecently arisen as a key point in CLL integrating cytogenetic alterations and mutations in a dynamic model that improve ourunderstanding about its clinical course and relapse

1 Introduction

Chronic lymphocytic leukemia (CLL) is the most commonleukemia of adults in Western countries The clinical courseis highly variable ranging fromvery indolent cases to patientswith aggressive and rapidly progressing disease This hetero-geneity has important consequences which will impact onclinical approaches treatment strategies and finally survivaltimes from diagnosis [1]

Acquired genetic aberrations as in other types of cancerhave an important role in CLL pathogenesis Since the late1970s numerous genetic studies using a wide range of labora-tory techniques (conventional G-banding cytogenetics fluo-rescence in situ hybridizationmicrosatellite analysis to detectloss of heterozygosity Sanger sequencing genomic arraysand more recently next generation sequencing methodolo-gies among others) have identified a broad spectrum ofgenomic aberrations Overall taking into account all of these

data CLL is characterized by a relatively stable genome incomparison with other hematological malignancies or solidtumors At diagnosis 80of cases showbetween 0 and 2 copynumber alterations and the remaining 20 harbor ge3 [2 3]The most frequent chromosomal abnormalities are partiallosses of one affected chromosome such as deletions on 6q11q 13q or 17p gains of entire chromosomes such as trisomy12 are less frequent In addition balanced translocationscan also be detected in a proportion of cases [4] Sincethe late 1990s there is an evidence that certain cytogeneticabnormalities such as 11q or 17p deletions are associatedwith a poor clinical outcome and have become importantprognostic factors [2] However chromosomal aberrationsmay not be responsible for the whole clinical heterogeneityof CLL Mutations in certain genes as TP53 are accountablefor poor prognosis Recent studies using next generationsequencing techniques have allowed the identification ofnew genomic abnormalities such as NOTCH1 and SF3B1

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 435983 13 pageshttpdxdoiorg1011552014435983

2 BioMed Research International

mutations as well as BIRC3 disruptions which may explainpart of the clinical heterogeneity and open the door to newtherapeutic strategies

The aim of the present review is to summarize the maingenetic abnormalities identified in CLL patients to describetheir impact in daily clinical practice and to discuss therecent findings using novel techniques

2 Cytogenetic Aberrations withKnown Prognostic Value

21 13q14 Deletion Deletion of 13q14 region found in morethan 50 of CLL patients is the most common cytogeneticabnormality detected by fluorescence in situ hybridization(FISH) and has historically been associated with good prog-nosis During the last years several studies have revealedsome insights in the candidate genes located at 13q thatcould be responsible for CLL pathogenesis as well as in theprognostic heterogeneity of 13q-deleted patients

With regard to biologic basis underlying 13q deletionsmiR-15a and miR16-1 located in the minimal deleted region(MDR) have been described to exhibit a tumoral suppressorfunction in CLL [5 6] However miR-15a and miR16-1 arenot invariably included in 13q deletions and although theirexpression is decreased in several CLL patients a clearcorrelation with the number of deleted 13q alleles has notbeen found [7] Thereby besides these microRNAs othergenes located in 13q such as DLEU7 could cooperate inthe tumoral suppressor activity In addition it has beenextensively demonstrated that large 13q losses involving RB1(type I deletions) gene are related to shorter time to firsttreatment (TTFT) and overall survival (OS) than those smalldeletions encompassing only miR-15a and miR16-1 (type II)(Figure 1 and Table 1) [7ndash10]

In contrast to other recurrent abnormalities in CLL thepresence of biallelic losses in 13q has been described innearly 30 of 13q-deleted CLL patients [16] Biallelic 13qdeletions are characteristically small and do not involve RB1[7] nevertheless their clinical impact has been controversialSome authors hypothesized that they result from an evolutionof the monoallelic losses and therefore represent a moreaggressive abnormality [13 14 17ndash19] However we andothers did not find significant differences in the baselinecharacteristics and clinical outcome among CLL patientswith monoallelic or biallelic 13q deletions [13 20 21] It isworth noting that 13q14 region can be inactivated by othermechanisms such as copy neutral loss of heterozygosity [3]and epigenetic silencing by DNAmethylation of CpG islands[22] or histone deacetylation [23] Thus it is feasible toassume that the potential effect of the biallelic 13q losses onthe prognosis could bemasked either by the size of the deletedregion or the inactivation of the remaining allele by othermechanisms

Regarding the size of the abnormal clone detected byFISH it has been described that those patients with a higherpercentage of altered nuclei have a significantly shorter TTFTand OS The optimal cut-off point that defines a pooreroutcome of 13q deletion differs between published studies

Table 1 Prognostic subgroups and associated risk genetic factors inCLL at diagnosis

Category Associatedgenetic factors Therapeutic strategies

Very high riskdel(17p)lowastTP53mutationandorBIRC3mutation

p53-independent drugsBTK inhibitorsallogeneic stem celltransplantation

High risk

del(11q)lowastATMmutationandorNOTCH1mutationandorSF3B1mutation

FCR

Intermediate riskTrisomy 12Normal karyotypeand FISH

Not recommended

Low risk Isolated del(13q)lowast Not recommendedFCR fludarabine cyclophosphamide and rituximab lowasthigher percentagesof deleted nuclei have bad impact on prognosis (Tam et al 2009 [11]Hernandez et al 2009 [12] van Dyke et al 2010 [13] Dal Bo et al 2011 [14]Marasca et al 2013 [15] Puiggros et al 2013 [21])

[12ndash14 19 21] Indeed although the cut-off described rangedfrom 655 to 90 the percentage of 13q deletion hada predictive value as a continuous variable [13 19] Thusthose patients with isolated 13q deletion can be risk-stratifiedaccording to the percentage of altered cells by FISH (Table 1)

Biologic heterogeneity underlying clinical differencesobserved among 13q-deleted patients has been also demon-strated by gene expression profiling and miRNA analyses [824] Specific transcriptional profiles have been correlatedwithtwo subgroups of 13q deletion based on the size of deleted area(shortbiallelic versuswidemonoallelic)Thus those patientswith large 13q losses showed downregulation of ten genesincluding TPT1TCTP which is involved in prosurvival andgrowth signaling through inhibition of BAX-induced apop-tosis and overexpression of 53 genes Most of the upregulatedgenes (AMF GPI BSG LGALS1 PAK2 PARVB and VIMamong others) were involved in cell motility and adhesionregulation of cell proliferation tumor cell migration metas-tasis angiogenesis and apoptosis Interestingly deregulationof many relevant cellular pathways has also been shownin those patients with higher percentages of 13q deletion(above 80) Among them are remarkably the deregulationof several important miRNAs and overexpression of genesmainly involved in BCR signaling (eg SYK and CD79b)NF120581B signaling and prosurvival and antiapoptotic pathways(eg Wnt and RAS signaling) Of note the gene expressionpattern observed in patients with gt80 of 13q-deleted cellswas similar to the patients with 11q- and 17p- included in thestudy [24]

In all although heterogeneity of 13q deletion has beendemonstrated recent studies that integrate molecular andcytogenetic data keep on considering patients with isolated13q deletion as a very low-risk group [25 26] MoreoverJeromin et al found association with mutations in MYD88which have no apparent prognostic effect [25]

BioMed Research International 3

P27 (12p131)

MYF6 (12q2131)

CDK4 (12q141)MDM2 (12q15)

HIP1R (12q2431)

TP53 (17p131)17

MYCN (2p243)

REL (2p161)BCL11A (2p161)

SF3B1 (2q331)

2 2p25

2p13

17p13

17p11

Poor

Varia

ble

Goo

dIn

term

edia

tePo

or

11q221

11q231

BIRC3 (11q222)

ATM (11q223)

11 12

9

NOTCH1 (9q343)

t(1418)(q32q24)t(1419)(q32q24)Others

14

IGH (14q32)

8 13

TNFRSF10AB (8p213)

p232

p22p212

q1122q121q123q132q2111q2113q213q222q231q233q2412q2421q2423

q333q331q322q313q311

q222q2133

q2131q211

q1412q133q131q122q1212

q132q211q213q222q231q233q242

q311q313q3212

q322

q12

q2432q2423q2421q233q231q2133q2131

q211q143q141q132q1312

p1122p121p123p132p1332

p252p243p241p223p163p161p14p12

q121q141q143q221q232q241q243q312q321q323q332q34q361q372

q12

q342q333q331q313q311q2232q2133q2131q2113q2111

p12p132p211p213p222p23p242

q243q241q232q223q221

q143q141

q134q132

q121q1112p12

p141p143

p152p154

q252q243

q241q232

q2132

q212q12

p12

p132

q22

p12

MYC (8q2421)

t(814)(q24q32)t(822)(q24q11) t(28)(p12q24)

48 Mbp

51 Mbp

RB1

MIR15-AMIR16-1

t(13q14)Nonrecurrentpartners

Type I

Type II

Chromosomalregion

Chromosomalregion Chr Altered

genes Chr Altered genes

Prog

nosis

Prog

nosis

13q142

Figure 1Main genetic abnormalities with known prognostic significance in CLL Genetic abnormalities are grouped by chromosomes (Chr)In the chromosomal region section losses and gains are represented in red and blue bars respectively breakpoints for translocations aredepicted as green diamonds loci where recurrently mutated genes are located are shown in orange circles


22 Trisomy 12 Trisomy 12 is the third most frequentchromosomal aberration in CLL (10ndash20 of cases) and oftenappears as the unique cytogenetic alteration (40ndash60 ofcases with +12) Besides it can be associated with otherchromosomal aberrations including trisomies 18 and 19recurrent CLL deletions (eg 14q 13q 11q or 17p) and IGHtranslocations [2 27]

Trisomy 12 was considered as an intermediate riskmarkerin the hierarchical prognostic model initially proposed byDohner et al [2] However this category still remains quitecontroversial Whereas first studies often correlated trisomy12 with a more aggressive clinical course [28 29] recentpublications tend to include it in an intermediate or even low-risk category [26 30] Regardless it corresponds with a clin-ical heterogeneous entity Recently NOTCH1 has emerged asa strongly associated marker that presents a high mutationfrequency in +12 CLL patients especially in those having abad outcome (with unmutated IGHV genes andor ZAP70+)The higher frequency of mutated NOTCH1 as well as CD38or CD49d expression could explain at least in part the badprognosis of these subgroups of cases and thus the differentsurvival rates in the entire +12 cohort (Figure 1 and Table 1)[31ndash33] Trisomy 12 is mainly considered as a clonal drivermutation that occurs early inCLL evolution and facilitates theappearance of secondary chromosomal aberrations or muta-tions in genes as NOTCH1 TP53 and FBXW7 [34 35] Thusit has been shown that cases with +12 and mutated IGHVgenes could easily acquire an additional chromosome 19 [36]Recently this subgroup of patients has been associated withvery high CD38 expression (even more than +12 isolatedcases) which occurs exclusively in isotype-switched IgGcells a rare immunoglobulin variant in CLL [37] Atypicalmorphology and immunophenotype have also been relatedto trisomy 12 [31 38] Moreover higher frequencies of unmu-tated IGHV genes as well as IGHV1 and IGHV4-39 variantshave been described in patients carrying +12 [35 38 39]

Regarding the pathogenesis of trisomy 12 it has beendifficult to establish a set of candidate genes since theaffected region is the whole chromosome instead of a smallercritical region Nonetheless RNA and protein expressionanalysis have suggested a gene dosage effect [40ndash42] Asexpected trisomy 12 is associated with an upregulation ofgenes distributed along the whole chromosome such as P27CDK4 HIP1R MYF6 and MDM2 [42 43] HIP1R overex-pression has been proposed as the best potential surrogatemarker although its clinical relevance remains uncertain[43] Besides MDM2 is involved inp53 degradation thusits overexpression can lead to cell cycle deregulation inpatients harboring this alteration [44] In addition othergenes not located on chromosome 12 have been describedto be differentially expressed in this subgroup of patientsmainly overexpressed such as BAX or E2F1 E2F1 is a tran-scription factor associated with proliferation and its activityis regulated through kinases such asCDK4 located on 12q141Therefore a direct gene dosage-dependent upregulation ofCDK4 might contribute to E2F1 overexpression in trisomy12 patients which suggests an increased proliferative activityas a potential pathomechanism in the course of this chro-mosomal aberration [42] Furthermore CD200 and P2RY14

are underexpressed in trisomy 12 cases which suggests thatadditional transacting interactions might play an importantrole in the evolution of this group of CLL patients [43]However a detailed pathomechanism of trisomy 12 has notbeen fully elucidated (Figure 1)

23 11q23 Deletion Deletion of the long arm of chromosome11 is detected in 5ndash20 of CLL patients [2 15 45] Thesedeletions are highly variable in size being larger than 20megabases inmost cases [46 47]TheMDR includes 11q223-q231 chromosome bands thus harboring the ATM genein almost all cases as well as other genes including RDXFRDX1 RAB39 CUL5 ACAT NPAT KDELC2 EXPH2MRE11 H2AX and BIRC3 (Figure 1) Indeed cases can beclassified in ldquoclassical or large deletionrdquo (more common) andldquoatypical or small deletionrdquo (uncommon andmore frequentlyassociated with ATM mutations) It is remarkable that nohomozygous 11q deletions have been described Regardingthe association between del(11q) and other chromosomalabnormalities such cases show an increased copy numberalterations thus indicating genomic instability [15 48] ATMgene mutations have been largely studied in CLL patientswith del(11q) however they have been found in only 8ndash30of 11q- patients [49] indicating that other genes could play arole in the pathobiology of 11q deletions in CLL One of thesegenes is BIRC3 which is located near to ATM gene at 11q22BIRC3 disrupting mutations and deletions have been rarelydetected in CLL at diagnosis (4) but detected in 24 offludarabine-refractory CLL patients (Figure 1) Interestinglyprogressive but fludarabine-sensitive patients did not showBIRC3 aberrations suggesting that BIRC3 genetic lesionsare specifically associated with a chemorefractory CLLphenotype [50] In addition it is remarkable that patientswith BIRC3 lesions are mutually exclusive with CLL patientsharboring TP53 abnormalities However a recent study byRose-Zerilli et al has shown that ATMmutations rather thanBIRC3 deletion andor mutation had impact on overall andprogression-free survival in 11q-deleted CLL patients treatedwith first-line therapy [51]

From a clinical point of view CLL patients with del(11q)are characterized by large and multiple lymphadenopathiesand have been associated with poor prognostic factorssuch as unmutated IGHV genes Regarding the prognos-tic significance the presence of del(11q) implies clinicallyprogressive disease in almost all cases In addition those11q- cases have been associated with shorter TTFT shorterremission durations and shorter OS following standardchemotherapy compared to nondeleted 11q (and nondeleted17p) cases [52] However more recent treatments based onchemoimmunotherapymay overcome the adverse prognosticsignificance of 11q deletion in previously untreated patientsIt has been reported that del(11q) does not have impact onprogression-free survival (PFS) however there is still a lackof information regarding long-term OS studies Moreovergenetic heterogeneity displayed in patients with del(11q) mayimpact on long-term clinical outcome (Table 1) [53]

24 17p13 Deletion Deletion of 17p is found in approximately3ndash8 of CLL patients at diagnosis [2 54 55] However it can


account for up to 30 in patients treated with chemotherapyand undergo refractory CLL [55 56] Thus it is one ofthe most frequently acquired aberrations triggered aftertreatment not only in CLL but also in other non-Hodgkinrsquoslymphomas such us mantle cell lymphoma or diffuse large B-cell lymphoma

Patients with 17p deletion have always been included intothe highest risk prognostic category showing the shortest OSand PFS This finding can be explained not only because ofthe cell-cycle deregulation caused by the loss of TP53 but alsothe usual requirement of chemotherapy both independentpredictors of a reduced OS and PFS (Table 1) [26 57]Nonetheless recent studies have shown clinical heterogeneityin 17p- patients according to the appearance of this abnor-mality during follow-up as an early event (de novo) or morefrequent as a secondary alteration [34] Patients with de novo17p- have a longer median OS (4-5 years) whereas thosewho acquired 17p- during clonal evolution have a notablydecreased survival (1ndash15 years) [11] Another important factorthat stratifies 17p deletion patients in different risk subgroupsis the percentage of nuclei altered by FISH The cut-off valuefor the percentage of 17p-deleted nuclei that predicted pooreroutcomewas initially established at 3 [58] while subsequentstudies increased the cut-off levels up to 25 [11 54 59 60]However it has recently been demonstrated that the clonesize has a negative impact on OS and response to treatmentnot only at different cut-off levels but also as a continu-ous variable [54] Strikingly latest investigations based onultradeep next generation sequencing were able to detectTP53 mutations in small CLL subclones that were missed bySanger sequencing due to their very low frequency Patientsharboring small TP53-mutated subclones also showed a poorsurvival These minority subclones became the predominantpopulation over time and prognosticated the development ofchemorefractoriness showing the importance of TP53 as adriver mutation [61]

It has been shown that mutations in TP53 are frequentlydetected in the remaining allele of 17p- CLL patients appear-ing in more than 75 of cases This is in contrast with thelow frequency of TP53 mutations in patients without 17pdeletion andmay reflect a selective pressure for cells carryingbiallelic inactivation of TP53 [62] Patients harboring bothabnormalities have a significantly poorer outcome withshorter OS and PFS and lower response rates than those withTP53 mutation or deletion of a single 17p allele [63 64]Nonetheless del(17p) in the absence ofmutatedTP53 and viceversa has also a negative effect on prognosis which pointsthat monoallelic inactivation of TP53 may be enough forresistance to treatment and clonal selection [63 64] Anothermechanism that can trigger the dysfunction of TP53 is theoverexpression ofMDM2 a p53-specific ubiquitin ligase thatmediates the degradation of p53 and has a higher expressionin 50 to 70 of patients [44] MDM2 overexpressioninvolves the repression of a large number of p53-dependentgenes and miRNAs including miR-34a a downstream effec-tor of p53 Although miR-34a expression is highly variablein nonaltered TP53 cases CLL cells from patients harboringTP53 mutations deletions or MDM2 overexpression areassociated with lower levels of miR-34a As this microRNA

is involved in the regulation of senescence apoptosis and cellcycle arrest a more aggressive course of the disease can becorrelated with miR-34a underexpression [65] In summaryalterations not only in TP53 but along the whole p53 axis leadto decreased overall survival and therapy resistance in CLL

CLL patients with 17p- have also been associated withatypical immunophenotype with a higher intensity of CD20FMC7 CD79b and surface Ig [31] In addition an increasedexpression of CD38 ZAP-70 and unmutated IGHV wasreported in 17p- cases which agrees with the poor prognosisof this group of patients [31 66 67] Other studies havedemonstrated a significant correlation between 17p- and 4p-18p- 20p- or chromosome 8 alterations (8p- or 8q+) [30 68]Thus TP53mutation17p- is correlated with a higher geneticcomplexity Nevertheless the acquisition of these aberrationsduring the progression of the illness and their precise effecthas not been fully elucidated

The extent of the 17p13 deletion often encompasses mostof the chromosome 17 short arm and is invariably associatedwith loss of TP53 as confirmed by FISH (Figure 1) The17p- subgroup displays the highest number of differentiallyexpressed genes affecting apoptosis cell cycle regulation andBCR signaling Underexpression of TP53 CCND3 BCL2SYK ATM TCL PI3K CCND1 and AID and overexpressionof P2MYC andAICLwere reported in this group of patientsindicating a remarkable genetic instability As expected TP53is themost significantly downregulated gene which underliesthe molecular mechanism that confers a poor response toalkylating agents and purine analogs although the concomi-tant loss of other tumor suppressor genes could be responsiblefor the highly adverse prognostic relevance of this subgroup[42 69 70]

The standard treatment for CLL is based on fludarabine-cyclophosphamide (FC) or fludarabine-cyclophosphamide-rituximab (FCR) regimens However patients harboring 17pdeletion andor TP53 mutations do not respond to thesetherapies In order to improve survival of nonrespondingpatients a wide spectrum of new drugs acting indepen-dently of p53 either as sole agents or combined have beentested including flavopiridol lenalidomide alemtuzumabalemtuzumabcorticosteroids and rituximabcorticosteroids[71] Recently inhibitors of key pathways in tumor B-cell physiopathology have arisen as promising new drugsAmong them dinaciclib (a cyclin-dependent kinase (CDK)inhibitor) ONO-4059 (a Brutonrsquos tyrosine-kinase (BTK)inhibitor) ABT-199 (a Bcl-2 inhibitor) and overall ibrutinib(another BTK inhibitor) have demonstrated a significantactivity in CLL [72ndash75] Up to now allogeneic stem celltransplantation was the suggested strategy for patients with17p- who had achieved a complete remission Nonethelesswith the confirmed activity of ibrutinib this strategy shouldbe reconsidered (Table 1) [71]

3 Other Abnormalities Described byConventional G-Banding Cytogenetics

Initial cytogenetic studies in CLL were highly limited bythe low mitotic rate of tumoral cells in culture [76] Indeed


interphase FISH analyses have been implemented as the goldstandard for cytogenetic risk stratification of CLL patients [2]Nonetheless detection of abnormalities by FISH is limited tothe probes used and underestimates the true complexity andheterogeneity of chromosomal aberrations in CLLThe use ofnew B-cell mitogens such as CD40-ligand or CpG oligonu-cleotide and interleukin-2 improves the growth of CLL cellsin culture increasing the detection rate of chromosomalabnormalities up to 80 of patients [77ndash80] By this methodit was demonstrated that 25ndash37 of patients showing noaberrations by FISH carried chromosomal abnormalities notcovered by the standard FISH panel (which detects trisomy 12and deletions of 11q 13q and 17p) [78 81] These additionalabnormalities otherwise not identified by FISH do notcorrelate with other poor prognostic factors including CD38or ZAP70 positivity and IGHV mutational status How-ever these abnormal karyotypes were strongly correlated toadvanced CLL stages and treatment requirement as wellas to worse prognosis in terms of shorter TTFT and OS[81] Despite the high heterogeneity of the abnormalitiesdetected several studies have demonstrated that the numberof abnormalities found by CGC can be correlated with theclinical outcome of CLL patients [4 82ndash85]

31 Chromosomal Translocations In contrast to othermatureB-cell neoplasms CLL is not characterized by the presenceof specific chromosomal translocations However it hasbeen described that 32ndash42 of CLL patients carry a widerange of translocations when studied by CGC [4 82 86]The prognostic significance of these chromosomal rear-rangements has been controversial Although it was initiallydescribed that translocations were associated with poor out-come independently of the number of rearrangements [86]more recent studies restricted the poor prognosis to thosecases harboring translocations in the context of a complexkaryotype or unbalanced translocations [4 82] Unbalancedtranslocations preserved its prognostic significance evenwhen analyzed in the 17p- group of patients [82] Balancedtranslocations involving IGH are uncommon in CLL (4ndash9of patients) [87] nonetheless some IGH translocations havebeen extensively characterized in the literature Although itwas initially defined that CLL patients with IGH transloca-tions were associated with poorer outcome and should beconsidered as a distinct prognostic group [87] subsequentstudies revealed that the chromosome partner involved inthe translocation could be relevant for the outcome Thus ithas been described that t(14 19) which involves BCL3 locusis associated with the presence of trisomy 12 and complexcytogenetics unmutated IGHV atypical CLL morphologyand phenotype and inferior prognosis On the contrary CLLpatients with IGHBCL2 have not shown association withcomplex karyotype or aggressive features that could triggera poorer outcome of this subgroup of IGH-translocatedpatients (Figure 1) [88] Translocations involving MYC withIG or non-IG partners are present in less than 1 of CLL butidentify a subgroup of CLL patients with higher incidenceof poor prognostic features compared with general CLLpopulation (Figure 1) [89 90] Moreover as prolymphocytesare detected in most of these cases it has been postulated

that MYC translocations could be a secondary event with atransforming role in CLL [89 90] Chromosome 13q is alsorecurrently translocated in CLL indeed 10 of the del(13q)identified by FISH are associated with 13q14 translocationsdetectable by CGC [91] It is accepted that 13q14 has multiplechromosome partners and that the consequence of theserearrangements is the loss of a tumor suppressor gene in13q14 [47] Indeed deletion of D13S319 locus has beenextensively evidenced in nearly all the cases described inthe literature (Figure 1) [47 91 92] The impact that 13qtranslocations could have on the prognosis of 13q deletionis controversial While some authors suggested that it couldrepresent a more aggressive disease with higher incidence ofRB1 deletion [91 92] our group has found RB1 deletion ratessimilar to large cohorts of unselected CLL patients with 13qdeletion (20ndash25) (personal observation) Translocations in13q are apparently balanced by CGC and several studies haveproven that balanced rearrangements do not imply a worseprognosis in CLL [4 82 86] Although it was described ina limited number of patients some authors suggested thatpoor prognosis of TP53 deletions could be modified when17p loss was caused by recurrent 17p translocations Thusdic(8 17)(p11 p11) was described in four CLL patients but stillhave an unclear clinical impact [93] while dic(17 18)(p112p112) was detected in 13 of 1213 patients studied and wasassociated with early age at diagnosis and accelerated diseaseprogression [94] Altogether chromosomal translocationsper se do not confer a bad outcome in CLL However somerecurrent rearrangements involving genes such as BCL3MYC or the 17p arm should be considered as poor prognosticindicators in the genetic risk stratification of patients

32 Complex Karyotypes Complex karyotypes (CK) definedas the presence of three or more chromosomal abnormalitiesare detected in nearly 16 of patients [4 78] and have beenassociated with unmutated IGHV status and CD38 expres-sion [78] Regarding prognostic significance CK predictedshortened TTFT and OS in CLL patients treated with savagetherapies including 2-chloro-21015840-deoxyadenosine (CdA) [8284] Shorter OS was observed in patients with relapsed andrefractory CLL treated with flavopiridol (a CDK inhibitor)[85] As a continuous variable the number of karyotypicabnormalities also predicted shorter event free survival(EFS) and OS in CLL patients who underwent allogeneichematopoietic stem cell transplantation (HSCT) followingreduced-intensity conditioning [83] being five abnormalitiesthe cut-off with the highest predictive value Of note a highlysignificant association between complex aberrant karyotypesand 11q or 17p deletions has been described [78 83] Althoughit could be assumed that the prognostic significance of CK iscaused by the association with these aberrations Jaglowski etal proved that karyotypic complexity retained its predictivevalue in EFS and OS even when only patients with high-risk FISH abnormalities were considered [83] MoreoverOuillette et al demonstrated that genomic complexity in CLLwas a consequence of an impaired DNA double-strand breakresponse due to multiple gene defects including not onlyTP53 but also ATM and other genes located in 11q or RB1gene located at 13q14 [95] The impact of CGC results in the


outcome of CLL patients as well as the multigenic origin ofthe genomic complexity in CLL suggest that CGC shouldbe implemented in the clinical practice to identify a subsetof patients with clinical and prognostic characteristics thatshould be considered for the design of risk-adapted treatmentstrategies

4 Cytogenetic Alterations Detected byGenomic Arrays

Despite being one of the first techniques used for screening ofchromosomal alterations in CLL CGC studies are limited bythe requirement of dividing cells in culture and FISH analysesonly offer a vision of the genome limited to the specificprobes used Microarray-based technologies have shown theability to allow a high-resolution genome-wide explorationfor allelic copy number gains and losses in CLL Initial studiescompared arrays and FISH analyses in the identification ofthe known recurrent CLL alterations Overall concordancesranging from 79 to 98 were described [48 96ndash99] Themajority of discordant results were due to the lower sensitivityof genomic arrays thus a cut-off point for the sensitivityof 20ndash30 of abnormal cells was fixed for different arrayplatforms [48 99ndash101] However subsequent studies pointedout that some deletions smaller than the probes used inthe FISH analyses could be only detected by arrays [102]and algorithms based on the percentage of tumoral cellsin peripheral blood have been suggested to optimize thedetection of genomic abnormalities [96 103]

On the other hand genomic array studies have allowedthe characterization of the size and the minimal deletedregion of known CLL abnormalities otherwise not possi-ble by studying CLL FISH panel Hence poorer outcomewas described for those 13q losses comprising not onlyDLEU2MIR15AMIR16-1 genes but also RB1 in the deletedarea (Figure 1) [7 10] Gunn et al described on their array-CGH analyses the multigenic nature of 11q deletions and theexistence of a minority of 11q losses that did not involveATM and could be missed by standard FISH probes [46]Deletions of 6q previously described in 3ndash6of CLL patientsby CGC and FISH [104 105] have also been identified inseveral genomic array studies with a detection rate rangingfrom 3 to 17 [97 102 106] In contrast to other knownabnormalities genomic array studies have pointed out thehigh heterogeneity of del(6q) and the impossibility to definean MDR for all patients Edelmann et al defined a regionof 25Mb at 6q21 that was affected in 80 of 6q- patientshowever no specific gene has been identified as responsiblefor the 6q- pathogenesis [102]

In addition recurrent CLL abnormalities not includedin the FISH panel which were cryptic or identified in verylow frequency by CGC have been widely described in thegenomic array studies Schwaenen et al initially described 2pgains includingMYCN gene in a low proportion of CLL casesThese cases showed a significant increase ofMYCN transcriptsuggesting a role in the pathogenesis of the disease [100]Subsequent studies confirmed this overexpression and alsohighlighted the involvement ofREL andMSH2 genes inmany

of the 2p gains However none of these genes showed differ-ential expression levels in the affected patients [106] Regard-ing prognostic impact detection of 2p gains increased up to28 of patients in untreated Binet BC patients and it hasbeen postulated that 2p gains are a secondary event associatedwith a shorter OS and an increased risk of transformation toRichter syndrome (Figure 1) [106 107] An evenmore aggres-sive course was defined for those patients with associationbetween 2p gains and the poor-prognosis 11q deletions whichtriggered combination of MYCN overexpression and ATMdownregulation [98] Abnormalities in chromosome 8 (8plosses and 8q gains) described by genomic arrays have beenalso pointed out as prognosticmarkers inCLL Although theywere identified in only 2ndash5 of general CLL population anincreased frequency of 8p and 8q abnormalities was observedin 17p- patients up to 80 and 44 respectively An inde-pendent association with shorter OS was described for theseabnormalities even when only 17p- patients were considered(Figure 1) [107 108] Other small recurrent abnormalitieswith unclear prognostic significance have been identifiedin genomic arrays studies thus submicroscopic deletionsin 22q11 and gains of 20q1312 were described in 15 and19 of CLL patients respectively Both abnormalities showedrelated gene expression changes revealing the high diversityof genomic aberrations in CLL and identifying new candidategenes involved in the pathogenesis of the disease [109 110]

Apart from recurrently altered regions several authorshave associated the complexity detected by genomic arrayswith either shorter TTFT worse response to therapy orshorter OS [30 48 97 101 103] More recently the phe-nomenon of chromothripsis in which hundreds of genomicrearrangements involving localized genomic regions occur ina single cellular crisis has been defined in at least 2-3 ofall cancers [111] Edelmann et al studied 353 CLL patientsby genomic arrays identifying chromotripsis defined as thepresence of at least ten switches between two or three copynumber states on an individual chromosome in seven ofthem Notably patients with chromothripsis had inferior PFSand OS as well as high frequencies of unmutated IGHV andhigh-risk genomic aberrations [102]

Overall results reported in the literature have demon-strated that microarray platforms are a valuable tool forgenomic study of CLL and the identification of novel aberra-tionswhichmay be cryptic by conventional techniques Aber-rations identified by arrays could be useful for a more accu-rate risk stratification of CLL patients and shed light on theknowledge of CLL pathogenesis However its incorporationin the diagnostic routine has been limited by several reasonsincluding the lower sensitivity in the detection of known poorprognostic abnormalities the still unknown significance ofmost of the small aberrations identified by genomic arraysor the inability to detect balanced aberrations which couldbe essential for the differential diagnosis with other matureB-cell neoplasms [99]

5 Clonal Evolution

Clonal evolution is a key point of CLL development andrelapse A recent whole-genome sequencing study identified


two types of driver mutations in CLL ones which appearas early events and were found as predominantly clonal(eg heterozygous 13q deletion trisomy 12 or MYD88 andNOTCH1 mutations) whereas others appear later in thecourse of the disease as secondary events and were foundmainly subclonal (eg TP53 ATM SF3B1 mutations andhomozygous 13q deletion) [34] Deletions in 17p and 11q havebeen described both as late or early events which couldexplain the heterogeneity of these subgroups of patients [11112] It was also demonstrated that chemotherapy triggersclonal evolution by favoring the appearance and dominationof subclones with driver mutations (such as TP53 or SF3B1)which proliferate and replace the other subclones over time[34] Nonetheless it may take months to years for a newsubclone to fully substitute those previous established [113]Clonal devolution defined as the disappearance of one ormore clonal aberrations at follow-up can also be observed intreated patients [55 114 115]

Both FISH and CGC are useful and complementarymethods to study clonal evolution in CLL samples HoweverFISH analyses were found to be more precise than CGC inthe detection of small cytogenetic abnormalities speciallydel(13q) and del(17p) [55] A wide range of frequencies ofclonal evolution has been described (10 to 45) being themost frequently acquired abnormalities detected by thesetechniques high-risk aberrations (17p and 11q deletions) andmono- and biallelic deletions of 13q [55 116] Recently whole-genome sequencing methods which can detect thousandsof somatic mutations per subclone revealed novel earlyand late CLL driver mutations [34 113] Nevertheless theimpossibility of applying this methodology in large cohortsof patients still leaves much to be elucidated As for theclinical relevance it still remains quite controversial if clonalevolution has a clear impact on survival A prognostic valuefor the acquisition of new genetic aberrations by itself has notbeen described however a bad prognosis was observed whenhigh-risk lesions were acquired [55]

6 New Genomic Technologies andFuture Perspectives

As scientific knowledge about genetics and CLL progressesnew powerful technologies have arisen paving the wayfor promising findings In the last years next generationsequencing studies have improved our understanding aboutthe abnormal physiopathology of tumoral B-cells as well ascontributed to redefine the traditional prognostic subgroupsIn addition to the previously well-characterized TP53 muta-tion novel somatic lesions with clinical significance havebeen detected most of which have already been mentionedin the present review Among them alterations in NOTCH1SF3B1 BIRC3 ATM and MYD88 were recurrently foundappearing in 3ndash15 of CLL patients either combined or assolely lesions [25 26 117 118]The appearance of these muta-tions is a consequence of the dynamic dialogue between CLLcells andmicroenvironment selective pressures whichwidelydetermines clonal evolution and response to treatment [34]

Prognosis prediction models usually employed to stratifyCLL patients include clinical factors (mainly based on the

lymphocyte doubling time and Rai and Binet staging sys-tems) molecular markers (expression of CD38 ZAP-70 andIGHV mutational status) and chromosomal abnormalitiesWith the new findings provided by NGS the cytogeneticmodel was proposed to be refined by integrating the analysisof recurrent gene mutations since most of them demon-strated to have a clinical independent impact on patientsurvival In a recent study published by Rossi et al a four-category model was proposed high risk (patients harboringdel(17p)TP53 mutation andor BIRC3 mutation) interme-diate risk (harboring del(11q) NOTCH1 mutation andorSF3B1 mutation) low risk (harboring trisomy 12 or normalkaryotype) and very low risk (if del(13q) is present as thesole abnormality) (Table 1) In addition the proportion of theabnormal clone is gaining importance in the stratificationof already defined groups as several studies have reporteddifferent outcomes in patients with high or low percentagesof nuclei harboring 13q- 11q- and 17p- by FISH [11 1215] In conclusion the current prognostic models basedon genetic abnormalities are nowadays subject to changeas new cytogenetic and mutational findings are revealedcontributing to refine better and better these approaches

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work has been supported by the following grantsPI1101621 from Fondo de Investigacion Sanitaria (FIS)Instituto de Salud Carlos III Spanish Ministry of Economyand Competitivity RD1200360044 from Red Tematicade Investigacion Cooperativa en Cancer (RTICC) FEDER2009SGR541 from Generalitat de Catalunya G Blanco wasfunded by a grant from La Caixa Foundation

References

[1] M Hallek B D Cheson D Catovsky et al ldquoGuidelines forthe diagnosis and treatment of chronic lymphocytic leukemiaa report from the International Workshop on Chronic Lym-phocytic Leukemia updating the National Cancer InstitutemdashWorking Group 1996 guidelinesrdquo Blood vol 111 no 12 pp5446ndash5456 2008

[2] H Dohner S Stilgenbauer A Benner et al ldquoGenomic aberra-tions and survival in chronic lymphocytic leukemiardquo The NewEngland Journal of Medicine vol 343 no 26 pp 1910ndash19162000

[3] S N Malek ldquoThe biology and clinical significance of acquiredgenomic copy number aberrations and recurrent gene muta-tions in chronic lymphocytic leukemiardquo Oncogene vol 32 no23 pp 2805ndash2817 2013

[4] P Baliakas M Iskas A Gardiner et al ldquoChromosomal translo-cations and karyotype complexity in chronic lymphocyticleukemia a systematic reappraisal of classic cytogenetic datardquoTheAmerican Journal of Hematology vol 89 no 3 pp 249ndash2552014


[5] G A Calin C D Dumitru M Shimizu et al ldquoFrequentdeletions and down-regulation of micro-RNA genes miR15 andmiR16 at 13q14 in chronic lymphocytic leukemiardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 99 no 24 pp 15524ndash15529 2002

[6] U Klein M Lia M Crespo et al ldquoThe DLEU2miR-15a16-1 cluster controls B cell proliferation and its deletion leads tochronic lymphocytic leukemiardquo Cancer Cell vol 17 no 1 pp28ndash40 2010

[7] P Ouillette H Erba L Kujawski M Kaminski K Sheddenand S N Malek ldquoIntegrated genomic profiling of chroniclymphocytic leukemia identifies subtypes of deletion 13q14rdquoCancer Research vol 68 no 4 pp 1012ndash1021 2008

[8] L Mosca S Fabris M Lionetti et al ldquoIntegrative genomicsanalyses reveal molecularly distinct subgroups of B-cell chroniclymphocytic leukemia patients with 13q14 deletionrdquo ClinicalCancer Research vol 16 no 23 pp 5641ndash5653 2010

[9] P Ouillette R Collins S Shakhan et al ldquoThe prognosticsignificance of various 13q14 deletions in chronic lymphocyticleukemiardquo Clinical Cancer Research vol 17 no 21 pp 6778ndash6790 2011

[10] H Parker M J J Rose-Zerilli A Parker et al ldquo13q deletionanatomy and disease progression in patients with chroniclymphocytic leukemiardquo Leukemia vol 25 no 3 pp 489ndash4972011

[11] C S Tam T D ShanafeltWGWierda et al ldquoDe novo deletion17p131 chronic lymphocytic leukemia shows significant clinicalheterogeneity the M D Anderson and Mayo Clinic experi-encerdquo Blood vol 114 no 5 pp 957ndash964 2009

[12] J A Hernandez A E Rodrıguez M Gonzalez et al ldquoA highnumber of losses in 13q14 chromosome band is associated witha worse outcome and biological differences in patients with B-cell chronic lymphoid leukemiardquo Haematologica vol 94 no 3pp 364ndash371 2009

[13] D L van Dyke T D Shanafelt T G Call et al ldquoA comprehen-sive evaluation of the prognostic significance of 13q deletionsin patients with B-chronic lymphocytic leukaemiardquoThe BritishJournal of Haematology vol 148 no 4 pp 544ndash550 2010

[14] M Dal Bo F M Rossi D Rossi et al ldquo13q14 deletion size andnumber of deleted cells both influence prognosis in chroniclymphocytic leukemiardquo Genes Chromosomes and Cancer vol50 no 8 pp 633ndash643 2011

[15] RMarasca RMaffei SMartinelli et al ldquoClinical heterogeneityof de novo 11q deletion chronic lymphocytic leukaemia prog-nostic relevance of extent of 11q deleted nuclei inside leukemicclonerdquoHematological Oncology vol 31 no 2 pp 348ndash355 2013

[16] K S Reddy ldquoChronic lymphocytic leukaemia profiled forprognosis using a fluorescence in situ hybridisation panelrdquoTheBritish Journal of Haematology vol 132 no 6 pp 705ndash7222006

[17] G W Dewald S R Brockman S F Paternoster et al ldquoChro-mosome anomalies detected by interphase fluorescence in situhybridization correlation with significant biological features ofB-cell chronic lymphocytic leukaemiardquo The British Journal ofHaematology vol 121 no 2 pp 287ndash295 2003

[18] C Chena J S Avalos R F Bezares et al ldquoBiallelic deletion13q143 in patients with chronic lymphocytic leukemia cyto-genetic FISH and Clinical Studiesrdquo The European Journal ofHaematology vol 81 no 2 pp 94ndash99 2008

[19] E M Orlandi P Bernasconi C Pascutto et al ldquoChroniclymphocytic leukemia with del13q14 as the sole abnormality

dynamic prognostic estimate by interphase-FISHrdquo Hematolog-ical Oncology vol 31 no 3 pp 136ndash142 2013

[20] R Garg W Wierda A Ferrajoli et al ldquoThe prognostic differ-ence of monoallelic versus biallelic deletion of 13q in chroniclymphocytic leukemiardquo Cancer vol 118 no 14 pp 3531ndash35372012

[21] A Puiggros J Delgado A Rodriguez-Vicente et al ldquoBialleliclosses of 13q do not confer a poorer outcome in chroniclymphocytic leukaemia analysis of 627 patients with isolated13q deletionrdquoThe British Journal of Haematology vol 163 no 1pp 47ndash54 2013

[22] D Mertens S Wolf C Tschuch et al ldquoAllelic silencing at thetumor-suppressor locus 13q143 suggests an epigenetic tumor-suppressor mechanismrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 103 no 20 pp 7741ndash7746 2006

[23] D Sampath C Liu K Vasan et al ldquoHistone deacetylasesmediate the silencing of miR-15a miR-16 and miR-29b inchronic lymphocytic leukemiardquo Blood vol 119 no 5 pp 1162ndash1172 2012

[24] A E Rodrıguez J A Hernandez R Benito et al ldquoMolecularcharacterization of chronic lymphocytic leukemia patients witha high number of losses in 13q14rdquo PLoS ONE vol 7 no 11 2012

[25] S Jeromin S Weissmann C Haferlach et al ldquoSF3B1 mutationscorrelated to cytogenetics and mutations in NOTCH1 FBXW7MYD88 XPO1 and TP53 in 1160 untreated CLL patientsrdquoLeukemia vol 28 no 1 pp 108ndash117 2014

[26] D Rossi S Rasi V Spina et al ldquoIntegrated mutational andcytogenetic analysis identifies new prognostic subgroups inchronic lymphocytic leukemiardquo Blood vol 121 no 8 pp 1403ndash1412 2013

[27] D Roos-Weil F Nguyen-Khac S Chevret et al ldquoMutationaland cytogenetic analyses Of 177 CLL patients with trisomy 12a retrospective study of the CLL french intergrouprdquo Blood vol122 no 21 p 4144 2013

[28] D G Oscier J Stevens T J Hamblin R M PickeringR Lambert and M Fitchett ldquoCorrelation of chromosomeabnormalities with laboratory features and clinical course inB-cell chronic lymphocytic leukaemiardquo The British Journal ofHaematology vol 76 no 3 pp 352ndash358 1990

[29] EMatutes D Oscier J Garcia-Marco et al ldquoTrisomy 12 definesa group of CLL with atypical morphology correlation betweencytogenetic clinical and laboratory features in 544 patientsrdquoTheBritish Journal of Haematology vol 92 no 2 pp 382ndash388 1996

[30] R Gunnarsson L Mansouri A Isaksson et al ldquoArray-basedgenomic screening at diagnosis and during follow-up in chroniclymphocytic leukemiardquo Haematologica vol 96 no 8 pp 1161ndash1169 2011

[31] S Quijano A Lopez A Rasillo et al ldquoImpact of trisomy12 del(13q) del(17p) and del(11q) on the immunophenotypeDNA ploidy status and proliferative rate of leukemic B-cells in chronic lymphocytic leukemiardquo Cytometry B ClinicalCytometry vol 74 no 3 pp 139ndash149 2008

[32] VGattei P BulianM I del Principe et al ldquoRelevance ofCD49dprotein expression as overall survival and progressive diseaseprognosticator in chronic lymphocytic leukemiardquo Blood vol111 no 2 pp 865ndash873 2008

[33] V Balatti A Bottoni A Palamarchuk et al ldquoNOTCH1 muta-tions in CLL associated with trisomy 12rdquo Blood vol 119 no 2pp 329ndash331 2012


[34] D A Landau S L Carter P Stojanov et al ldquoEvolutionand impact of subclonal mutations in chronic lymphocyticleukemiardquo Cell vol 152 no 4 pp 714ndash726 2013

[35] E Falisi E Novella C Visco et al ldquoB-cell receptor configu-ration and mutational analysis of patients with chronic lym-phocytic leukaemia and trisomy 12 reveal recurrent molecularabnormalitiesrdquo Hematological Oncology vol 32 no 1 pp 22ndash30 2014

[36] L Sellmann S Gesk C Walter et al ldquoTrisomy 19 is associatedwith trisomy 12 andmutated IGHV genes in B-chronic lympho-cytic leukaemiardquo The British Journal of Haematology vol 138no 2 pp 217ndash220 2007

[37] R Ibbotson A Athanasiadou L-A Sutton et al ldquoCoexistenceof trisomies of chromosomes 12 and 19 in chronic lymphocyticleukemia occurs exclusively in the rare IgG-positive variantrdquoLeukemia vol 26 no 1 pp 170ndash172 2012

[38] A Athanasiadou K Stamatopoulos A Tsompanakou et alldquoClinical immunophenotypic and molecular profiling of tri-somy 12 in chronic lymphocytic leukemia and comparison withother karyotypic subgroups defined by cytogenetic analysisrdquoCancer Genetics and Cytogenetics vol 168 no 2 pp 109ndash1192006

[39] C Lopez J Delgado D Costa et al ldquoDifferent distributionof NOTCH1 mutations in chronic lymphocytic leukemia withisolated trisomy 12 or associated with other chromosomalalterationsrdquo Genes Chromosomes and Cancer vol 51 no 9 pp881ndash889 2012

[40] D Winkler C Schneider A Krober et al ldquoProtein expressionanalysis of chromosome 12 candidate genes in chronic lympho-cytic leukemia (CLL)rdquo Leukemia vol 19 no 7 pp 1211ndash12152005

[41] C Haslinger N Schweifer S Stilgenbauer et al ldquoMicroar-ray gene expression profiling of B-cell chronic lymphocyticleukemia subgroups defined by genomic aberrations and VHmutation statusrdquo Journal of Clinical Oncology vol 22 no 19 pp3937ndash3949 2004

[42] D L Kienle C Korz B Hosch et al ldquoEvidence for distinctpathomechanisms in genetic subgroups of chronic lymphocyticleukemia revealed by quantitative expression analysis of cellcycle activation and apoptosis-associated genesrdquo Journal ofClinical Oncology vol 23 no 16 pp 3780ndash3792 2005

[43] E Porpaczy M Bilban G Heinze et al ldquoGene expressionsignature of chronic lymphocytic leukaemia with Trisomy 12rdquoThe European Journal of Clinical Investigation vol 39 no 7 pp568ndash575 2009

[44] E Konıkova and J Kusenda ldquoAltered expression of p53 andMDM2 proteins in hematological malignanciesrdquo Neoplasmavol 50 no 1 pp 31ndash40 2003

[45] T Zenz D Mertens R Kuppers H Dohner and S Stilgen-bauer ldquoFrom pathogenesis to treatment of chronic lymphocyticleukaemiardquo Nature Reviews Cancer vol 10 no 1 pp 37ndash502010

[46] S R Gunn M K Hibbard S H Ismail et al ldquoAtypical11q deletions identified by array CGH may be missed byFISH panels for prognostic markers in chronic lymphocyticleukemiardquo Leukemia vol 23 no 5 pp 1011ndash1017 2009

[47] A CGardinerMMCorcoran andDGOscier ldquoCytogeneticfluorescence in situ hybridisation and clinical evaluation oftranslocations with concomitant deletion at 13q14 in chroniclymphocytic leukaemiardquo Genes Chromosomes and Cancer vol20 no 1 pp 73ndash81 1997

[48] P Ouillette R Collins S Shakhan et al ldquoAcquired genomiccopy number aberrations and survival in chronic lymphocyticleukemiardquo Blood vol 118 no 11 pp 3051ndash3061 2011

[49] P Ouillette J Li R Shaknovich et al ldquoIncidence and clini-cal implications of ATM aberrations in chronic lymphocyticleukemiardquo Genes Chromosomes and Cancer vol 51 no 12 pp1125ndash1132 2012

[50] D Rossi M Fangazio S Rasi et al ldquoDisruption of BIRC3associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemiardquo Blood vol 119 no 12 pp2854ndash2862 2012

[51] M J Rose-Zerilli J Forster H Parker et al ldquoATM mutationrather than BIRC3 deletion andor mutation predicts reducedsurvival in 11q-deleted chronic lymphocytic leukemia datafrom the UK LRF CLL4 trialrdquoHaematologica vol 99 no 4 pp736ndash742 2014

[52] W G Wierda S OrsquoBrien X Wang et al ldquoMultivariable modelfor time to first treatment in patients with chronic lymphocyticleukemiardquo Journal of Clinical Oncology vol 29 no 31 pp 4088ndash4095 2011

[53] A-M Tsimberidou C Tam L V Abruzzo et al ldquoChemoim-munotherapy may overcome the adverse prognostic signifi-cance of 11q deletion in previously untreated patients withchronic lymphocytic leukemiardquo Cancer vol 115 no 2 pp 373ndash380 2009

[54] J Delgado B Espinet A C Oliveira et al ldquoChronic lympho-cytic leukaemia with 17p deletion a retrospective analysis ofprognostic factors and therapy resultsrdquo The British Journal ofHaematology vol 157 no 1 pp 67ndash74 2012

[55] E Wawrzyniak A Kotkowska J Z Blonski et al ldquoClonal evo-lution in CLL patients as detected by FISH versus chromosomebanding analysis and its clinical significancerdquo The EuropeanJournal of Haematology vol 92 no 2 pp 91ndash101 2014

[56] S Stilgenbauer T Zenz D Winkler et al ldquoSubcutaneousalemtuzumab in fludarabine-refractory chronic lymphocyticleukemia clinical results and prognostic marker analysesfrom the CLL2H study of the German Chronic LymphocyticLeukemia Study Grouprdquo Journal of Clinical Oncology vol 27no 24 pp 3994ndash4001 2009

[57] M Hallek K Fischer G Fingerle-Rowson et al ldquoAdditionof rituximab to fludarabine and cyclophosphamide in patientswith chronic lymphocytic leukaemia a randomised open-labelphase 3 trialrdquoThe Lancet vol 376 no 9747 pp 1164ndash1174 2010

[58] H Dohner K Fischer M Bentz et al ldquop53 gene deletionpredicts for poor survival and non-response to therapy withpurine analogs in chronic B-cell leukemiasrdquo Blood vol 85 no6 pp 1580ndash1589 1995

[59] D Oscier RWade Z Davis et al ldquoPrognostic factors identifiedthree risk groups in the LRF CLL4 trial independent oftreatment allocationrdquo Haematologica vol 95 no 10 pp 1705ndash1712 2010

[60] D Catovsky S Richards E Matutes et al ldquoAssessment offludarabine plus cyclophosphamide for patients with chroniclymphocytic leukaemia (the LRF CLL4 Trial) a randomisedcontrolled trialrdquo The Lancet vol 370 no 9583 pp 230ndash2392007

[61] D Rossi H Khiabanian V Spina et al ldquoClinical impact of smallTP53 mutated subclones in chronic lymphocytic leukemiardquoBlood vol 123 no 14 pp 2139ndash2147 2014

[62] T Zenz A Krober K Scherer et al ldquoMonoallelic TP53 inacti-vation is associatedwith poor prognosis in chronic lymphocytic


leukemia results from a detailed genetic characterization withlong-term follow-uprdquo Blood vol 112 no 8 pp 3322ndash3329 2008

[63] T Zenz D Vollmer M Trbusek et al ldquoTP53 mutation profilein chronic lymphocytic leukemia evidence for a disease spe-cific profile from a comprehensive analysis of 268 mutationsrdquoLeukemia vol 24 no 12 pp 2072ndash2079 2010

[64] D Gonzalez P Martinez R Wade et al ldquoMutational status ofthe TP53 gene as a predictor of response and survival in patientswith chronic lymphocytic leukemia results from the LRF CLL4trialrdquo Journal of Clinical Oncology vol 29 no 16 pp 2223ndash22292011

[65] D Asslaber J D Pinon I Seyfried et al ldquomicroRNA-34aexpression correlates with MDM2 SNP309 polymorphismand treatment-free survival in chronic lymphocytic leukemiardquoBlood vol 115 no 21 pp 4191ndash4197 2010

[66] L Z Rassenti S JainM J Keating et al ldquoRelative value of ZAP-70 CD38 and immunoglobulin mutation status in predictingaggressive disease in chronic lymphocytic leukemiardquo Blood vol112 no 5 pp 1923ndash1930 2008

[67] A Krober J Bloehdorn S Hafner et al ldquoAdditional genetichigh-risk features such as 11q deletion 17p deletion and V3-21 usage characterize discordance of ZAP-70 and VHmutationstatus in chronic lymphocytic leukemiardquo Journal of ClinicalOncology vol 24 no 6 pp 969ndash975 2006

[68] H C Rudenko M Else C Dearden et al ldquoCharacterisingthe TP53-deleted subgroup of chronic lymphocytic leukemiaan analysis of additional cytogenetic abnormalities detected byinterphase fluorescence in situ hybridisation and array-basedcomparative genomic hybridisationrdquo Leukemia amp Lymphomavol 49 no 10 pp 1879ndash1886 2008

[69] S Fabris L Mosca K Todoerti et al ldquoMolecular and transcrip-tional characterization of 17p loss in B-cell chronic lymphocyticleukemiardquo Genes Chromosomes and Cancer vol 47 no 9 pp781ndash793 2008

[70] M R Grever DM Lucas GW Dewald et al ldquoComprehensiveassessment of genetic and molecular features predicting out-come in patients with chronic lymphocytic leukemia resultsfrom the US Intergroup Phase III Trial E2997rdquo Journal ofClinical Oncology vol 25 no 7 pp 799ndash804 2007

[71] N Jain and S OrsquoBrien ldquoChronic lymphocytic leukemia withdeletion 17p emerging treatment optionsrdquoOncology vol 26 no11 pp 1067ndash1070 2012

[72] S Cheng J Ma A Guo et al ldquoBTK inhibition targets in vivoCLLproliferation through its effects onB-cell receptor signalingactivityrdquo Leukemia vol 28 no 3 pp 649ndash657 2014

[73] J A Burger ldquoBrutonrsquos Tyrosine Kinase (BTK) inhibitors inclinical trialsrdquo Current Hematologic Malignancy Reports vol 9no 1 pp 44ndash49 2014

[74] A J Johnson Y Y Yeh L L Smith et al ldquoThe novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotesapoptosis and abrogates microenvironmental cytokine protec-tion in chronic lymphocytic leukemia cellsrdquo Leukemia vol 26no 12 pp 2554ndash2557 2012

[75] M S Davis A Letai and J R Brown ldquoOvercoming stroma-mediated treatment resistance in chronic lymphocytic leukemiathrough BCL-2 inhibitionrdquo Leukemia amp Lymphoma vol 54 no8 pp 1823ndash1825 2013

[76] G Juliusson D G Oscier M Fitchett et al ldquoPrognosticsubgroups in B-cell chronic lymphocytic leukemia defined byspecific chromosomal abnormalitiesrdquoTheNew England Journalof Medicine vol 323 no 11 pp 720ndash724 1990

[77] F Dicker S Schnittger T Haferlach W Kern and C SchochldquoImmunostimulatory oligonucleotide-induced metaphasecytogenetics detect chromosomal aberrations in 80 of CLLpatients a study of 132 CLL cases with correlation to FISHIgVH status and CD38 expressionrdquo Blood vol 108 no 9 pp3152ndash3160 2006

[78] C Haferlach F Dicker S SchnittgerW Kern and T HaferlachldquoComprehensive genetic characterization of CLL a study on506 cases analysed with chromosome banding analysis inter-phase FISH IgVH status and immunophenotypingrdquo Leukemiavol 21 no 12 pp 2442ndash2451 2007

[79] N A Heerema J C Byrd P S Dal Cin et al ldquoStimulation ofchronic lymphocytic leukemia cells with CpG oligodeoxynu-cleotide gives consistent karyotypic results among laboratoriesa CLLResearchConsortium (CRC) StudyrdquoCancer Genetics andCytogenetics vol 203 no 2 pp 134ndash140 2010

[80] A Kotkowska E Wawrzyniak J Z Blonski T Robak andA Korycka-Wolowiec ldquoChromosomal aberrations in chroniclymphocytic leukemia detected by conventional cytogeneticswithDSP30 as a single agent comparisonwith FISHrdquo LeukemiaResearch vol 35 no 8 pp 1032ndash1038 2011

[81] G M Rigolin F Cibien S Martinelli et al ldquoChromosomeaberrations detected by conventional karyotyping using novelmitogens in chronic lymphocytic leukemia with ldquonormalrdquoFISH correlations with clinicobiologic parametersrdquo Blood vol119 no 10 pp 2310ndash2313 2012

[82] E van den Neste V Robin J Francart et al ldquoChromo-somal translocations independently predict treatment fail-ure treatment-free survival and overall survival in B-cellchronic lymphocytic leukemia patients treated with cladribinerdquoLeukemia vol 21 no 8 pp 1715ndash1722 2007

[83] S M Jaglowski A S Ruppert N A Heerema et al ldquoComplexkaryotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lym-phocytic leukaemiardquo The British Journal of Haematology vol159 no 1 pp 82ndash87 2012

[84] A Travella L Ripolles A Aventin et al ldquoStructural alterationsin chronic lymphocytic leukaemia Cytogenetic and FISHanalysisrdquo Hematological Oncology vol 31 no 2 pp 339ndash3472013

[85] J A Woyach G Lozanski A S Ruppert et al ldquoOutcomeof patients with relapsed or refractory chronic lymphocyticleukemia treated with flavopiridol impact of genetic featuresrdquoLeukemia vol 26 no 6 pp 1442ndash1444 2012

[86] C Mayr M R Speicher D M Kofler et al ldquoChromosomaltranslocations are associated with poor prognosis in chroniclymphocytic leukemiardquo Blood vol 107 no 2 pp 742ndash751 2006

[87] F Cavazzini J A Hernandez A Gozzetti et al ldquoChromosome14q32 translocations involving the immunoglobulin heavychain locus in chronic lymphocytic leukaemia identify a diseasesubset with poor prognosisrdquoTheBritish Journal of Haematologyvol 142 no 4 pp 529ndash537 2008

[88] N Put P Meeus B Chatelain et al ldquoTranslocation t(1418) isnot associated with inferior outcome in chronic lymphocyticleukemiardquo Leukemia vol 23 no 6 pp 1201ndash1204 2009

[89] N Put K van Roosbroeck P Konings et al ldquoChronic lym-phocytic leukemia and prolymphocytic leukemia with MYCtranslocations a subgroup with an aggressive disease courserdquoAnnals of Hematology vol 91 no 6 pp 863ndash873 2012

[90] Y O Huh K I-C Lin F Vega et al ldquoMYC translocationin chronic lymphocytic leukaemia is associated with increased


prolymphocytes and a poor prognosisrdquo The British Journal ofHaematology vol 142 no 1 pp 36ndash44 2008

[91] M Hruba P Dvorak L Weberova and I Subrt ldquoIndependentcoexistence of clones with 13q14 deletion at reciprocal translo-cation breakpoint and 13q14 interstitial deletion in chroniclymphocytic leukemiardquo Leukemia amp Lymphoma vol 53 no 10pp 2054ndash2062 2012

[92] S Struski C Helias C Gervais et al ldquo13q deletions in B-cell lymphoproliferative disorders frequent association withtranslocationrdquo Cancer Genetics and Cytogenetics vol 174 no2 pp 151ndash160 2007

[93] C Lopez T Baumann D Costa et al ldquoA new genetic abnor-mality leading to TP53 gene deletion in chronic lymphocyticleukaemiardquo The British Journal of Haematology vol 156 no 5pp 612ndash618 2012

[94] J A Woyach N A Heerema J Zhao et alldquoDic(1718)(p112p112) is a recurring abnormality in chroniclymphocytic leukaemia associated with aggressive diseaserdquoTheBritish Journal of Haematology vol 148 no 5 pp 754ndash7592010

[95] P Ouillette S Fossum B Parkin et al ldquoAggressive chroniclymphocytic leukemia with elevated genomic complexity isassociated with multiple gene defects in the response to DNAdouble-strand breaksrdquo Clinical Cancer Research vol 16 no 3pp 835ndash847 2010

[96] S R Gunn M S Mohammed M E Gorre et al ldquoWhole-genome scanning by array comparative genomic hybridizationas a clinical tool for risk assessment in chronic lymphocyticleukemiardquo The Journal of Molecular Diagnostics vol 10 no 5pp 442ndash451 2008

[97] D P OrsquoMalley C Giudice A S Chang et al ldquoComparison ofarray comparative genomic hybridization (aCGH) to FISH andcytogenetics in prognostic evaluation of chronic lymphocyticleukemiardquo International Journal of Laboratory Hematology vol33 no 3 pp 238ndash244 2011

[98] R Gunnarsson A Isaksson M Mansouri et al ldquoLarge but notsmall copy-number alterations correlate to high-risk genomicaberrations and survival in chronic lymphocytic leukemiaa high-resolution genomic screening of newly diagnosedpatientsrdquo Leukemia vol 24 no 1 pp 211ndash215 2010

[99] A Puiggros E PuigdecanetM Salido et al ldquoGenomic arrays inchronic lymphocytic leukemia routine clinical practice are weready to substitute conventional cytogenetics and fluorescencein situ hybridization techniquesrdquo Leukemia amp Lymphoma vol54 no 5 pp 986ndash995 2013

[100] C Schwaenen M Nessling S Wessendorf et al ldquoAuto-mated array-based genomic profiling in chronic lymphocyticleukemia development of a clinical tool and discovery ofrecurrent genomic alterationsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no4 pp 1039ndash1044 2004

[101] L Kujawski P Ouillette H Erba et al ldquoGenomic complex-ity identifies patients with aggressive chronic lymphocyticleukemiardquo Blood vol 112 no 5 pp 1993ndash2003 2008

[102] J Edelmann K Holzmann F Miller et al ldquoHigh-resolutiongenomic profiling of chronic lymphocytic leukemia reveals newrecurrent genomic alterationsrdquo Blood vol 120 no 24 pp 4783ndash4794 2012

[103] N E Kay J E Eckel-Passow E Braggio et al ldquoProgressive butpreviously untreatedCLLpatientswith greater arrayCGHcom-plexity exhibit a less durable response to chemoimmunother-apyrdquo Cancer Genetics and Cytogenetics vol 203 no 2 pp 161ndash168 2010

[104] S Stilgenbauer L Bullinger A Banner et al ldquoIncidence andclinical significance of 6q deletions in B cell chronic lympho-cytic leukemiardquo Leukemia vol 13 no 9 pp 1331ndash1334 1999

[105] A Cuneo G M Rigolin R Bigoni et al ldquoChronic lymphocyticleukemia with 6qmdashshows distinct hematological features andintermediate prognosisrdquo Leukemia vol 18 no 3 pp 476ndash4832004

[106] E Chapiro N Leporrier I Radford-Weiss et al ldquoGain of theshort arm of chromosome 2 (2p) is a frequent recurring chro-mosome aberration in untreated chronic lymphocytic leukemia(CLL) at advanced stagesrdquo Leukemia Research vol 34 no 1 pp63ndash68 2010

[107] A Rinaldi M Mian I Kwee et al ldquoGenome-wide DNAprofiling better defines the prognosis of chronic lymphocyticleukaemiardquo The British Journal of Haematology vol 154 no 5pp 590ndash599 2011

[108] F Forconi A Rinaldi I Kwee et al ldquoGenome-wide DNAanalysis identifies recurrent imbalances predicting outcome inchronic lymphocytic leukaemia with 17p deletionrdquo The BritishJournal of Haematology vol 143 no 4 pp 532ndash536 2008

[109] A E Rodrıguez C Robledo J L Garcıa et al ldquoIdentificationof a novel recurrent gain on 20q13 in chronic lymphocyticleukemia by array CGH and gene expression profilingrdquo Annalsof Oncology vol 23 no 8 pp 2138ndash2146 2012

[110] S R Gunn A R Bolla L L Barron et al ldquoArray CGHanalysis of chronic lymphocytic leukemia reveals frequentcrypticmonoallelic and biallelic deletions of chromosome 22q11that include the PRAME generdquo Leukemia Research vol 33 no9 pp 1276ndash1281 2009

[111] P J Stephens C D Greenman B Fu et al ldquoMassive genomicrearrangement acquired in a single catastrophic event duringcancer developmentrdquo Cell vol 144 no 1 pp 27ndash40 2011

[112] A Cuneo R Bigoni GM Rigolin et al ldquoLate appearance of the11q223-231 deletion involving the ATM locus in B-cell chroniclymphocytic leukemia and related disorders Clinico-biologicalsignificancerdquo Haematologica vol 87 no 1 pp 44ndash51 2002

[113] A Schuh J Becq S Humphray et al ldquoMonitoring chronic lym-phocytic leukemia progression by whole genome sequencingreveals heterogeneous clonal evolution patternsrdquoBlood vol 120no 20 pp 4191ndash4196 2012

[114] A Janssens N van Roy B Poppe et al ldquoHigh-risk clonalevolution in chronic B-lymphocytic leukemia single-centerinterphase fluorescence in situ hybridization study and reviewof the literaturerdquoThe European Journal of Haematology vol 89no 1 pp 72ndash80 2012

[115] S Stilgenbauer S Sander L Bullinger et al ldquoClonal evolutionin chronic lymphocytic leukemia acquisition of high-riskgenomic aberrations associated with unmutated VH resistanceto therapy and short survivalrdquoHaematologica vol 92 no 9 pp1242ndash1245 2007

[116] A Berkova Z Zemanova M Trneny et al ldquoClonal evolutionin chronic lymphocytic leukemia studied by interphase fluores-cence in-situ hybridizationrdquo Neoplasma vol 56 no 5 pp 455ndash458 2009

[117] V Quesada L Conde N Villamor et al ldquoExome sequencingidentifies recurrent mutations of the splicing factor SF3B1 gene


in chronic lymphocytic leukemiardquo Nature Genetics vol 44 no1 pp 47ndash52 2012

[118] X S Puente M Pinyol V Quesada et al ldquoWhole-genomesequencing identifies recurrent mutations in chronic lympho-cytic leukaemiardquo Nature vol 475 no 7354 pp 101ndash105 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


mutations as well as BIRC3 disruptions which may explainpart of the clinical heterogeneity and open the door to newtherapeutic strategies

The aim of the present review is to summarize the maingenetic abnormalities identified in CLL patients to describetheir impact in daily clinical practice and to discuss therecent findings using novel techniques

2 Cytogenetic Aberrations withKnown Prognostic Value

21 13q14 Deletion Deletion of 13q14 region found in morethan 50 of CLL patients is the most common cytogeneticabnormality detected by fluorescence in situ hybridization(FISH) and has historically been associated with good prog-nosis During the last years several studies have revealedsome insights in the candidate genes located at 13q thatcould be responsible for CLL pathogenesis as well as in theprognostic heterogeneity of 13q-deleted patients

With regard to biologic basis underlying 13q deletionsmiR-15a and miR16-1 located in the minimal deleted region(MDR) have been described to exhibit a tumoral suppressorfunction in CLL [5 6] However miR-15a and miR16-1 arenot invariably included in 13q deletions and although theirexpression is decreased in several CLL patients a clearcorrelation with the number of deleted 13q alleles has notbeen found [7] Thereby besides these microRNAs othergenes located in 13q such as DLEU7 could cooperate inthe tumoral suppressor activity In addition it has beenextensively demonstrated that large 13q losses involving RB1(type I deletions) gene are related to shorter time to firsttreatment (TTFT) and overall survival (OS) than those smalldeletions encompassing only miR-15a and miR16-1 (type II)(Figure 1 and Table 1) [7ndash10]

In contrast to other recurrent abnormalities in CLL thepresence of biallelic losses in 13q has been described innearly 30 of 13q-deleted CLL patients [16] Biallelic 13qdeletions are characteristically small and do not involve RB1[7] nevertheless their clinical impact has been controversialSome authors hypothesized that they result from an evolutionof the monoallelic losses and therefore represent a moreaggressive abnormality [13 14 17ndash19] However we andothers did not find significant differences in the baselinecharacteristics and clinical outcome among CLL patientswith monoallelic or biallelic 13q deletions [13 20 21] It isworth noting that 13q14 region can be inactivated by othermechanisms such as copy neutral loss of heterozygosity [3]and epigenetic silencing by DNAmethylation of CpG islands[22] or histone deacetylation [23] Thus it is feasible toassume that the potential effect of the biallelic 13q losses onthe prognosis could bemasked either by the size of the deletedregion or the inactivation of the remaining allele by othermechanisms

Regarding the size of the abnormal clone detected byFISH it has been described that those patients with a higherpercentage of altered nuclei have a significantly shorter TTFTand OS The optimal cut-off point that defines a pooreroutcome of 13q deletion differs between published studies

Table 1 Prognostic subgroups and associated risk genetic factors inCLL at diagnosis

Category Associatedgenetic factors Therapeutic strategies

Very high riskdel(17p)lowastTP53mutationandorBIRC3mutation

p53-independent drugsBTK inhibitorsallogeneic stem celltransplantation

High risk

del(11q)lowastATMmutationandorNOTCH1mutationandorSF3B1mutation

FCR

Intermediate riskTrisomy 12Normal karyotypeand FISH

Not recommended

Low risk Isolated del(13q)lowast Not recommendedFCR fludarabine cyclophosphamide and rituximab lowasthigher percentagesof deleted nuclei have bad impact on prognosis (Tam et al 2009 [11]Hernandez et al 2009 [12] van Dyke et al 2010 [13] Dal Bo et al 2011 [14]Marasca et al 2013 [15] Puiggros et al 2013 [21])

[12ndash14 19 21] Indeed although the cut-off described rangedfrom 655 to 90 the percentage of 13q deletion hada predictive value as a continuous variable [13 19] Thusthose patients with isolated 13q deletion can be risk-stratifiedaccording to the percentage of altered cells by FISH (Table 1)

Biologic heterogeneity underlying clinical differencesobserved among 13q-deleted patients has been also demon-strated by gene expression profiling and miRNA analyses [824] Specific transcriptional profiles have been correlatedwithtwo subgroups of 13q deletion based on the size of deleted area(shortbiallelic versuswidemonoallelic)Thus those patientswith large 13q losses showed downregulation of ten genesincluding TPT1TCTP which is involved in prosurvival andgrowth signaling through inhibition of BAX-induced apop-tosis and overexpression of 53 genes Most of the upregulatedgenes (AMF GPI BSG LGALS1 PAK2 PARVB and VIMamong others) were involved in cell motility and adhesionregulation of cell proliferation tumor cell migration metas-tasis angiogenesis and apoptosis Interestingly deregulationof many relevant cellular pathways has also been shownin those patients with higher percentages of 13q deletion(above 80) Among them are remarkably the deregulationof several important miRNAs and overexpression of genesmainly involved in BCR signaling (eg SYK and CD79b)NF120581B signaling and prosurvival and antiapoptotic pathways(eg Wnt and RAS signaling) Of note the gene expressionpattern observed in patients with gt80 of 13q-deleted cellswas similar to the patients with 11q- and 17p- included in thestudy [24]

In all although heterogeneity of 13q deletion has beendemonstrated recent studies that integrate molecular andcytogenetic data keep on considering patients with isolated13q deletion as a very low-risk group [25 26] MoreoverJeromin et al found association with mutations in MYD88which have no apparent prognostic effect [25]


P27 (12p131)

MYF6 (12q2131)

CDK4 (12q141)MDM2 (12q15)

HIP1R (12q2431)

TP53 (17p131)17

MYCN (2p243)

REL (2p161)BCL11A (2p161)

SF3B1 (2q331)

2 2p25

2p13

17p13

17p11

Poor

Varia

ble

Goo

dIn

term

edia

tePo

or

11q221

11q231

BIRC3 (11q222)

ATM (11q223)

11 12

9

NOTCH1 (9q343)

t(1418)(q32q24)t(1419)(q32q24)Others

14

IGH (14q32)

8 13

TNFRSF10AB (8p213)

p232

p22p212

q1122q121q123q132q2111q2113q213q222q231q233q2412q2421q2423

q333q331q322q313q311

q222q2133

q2131q211

q1412q133q131q122q1212

q132q211q213q222q231q233q242

q311q313q3212

q322

q12

q2432q2423q2421q233q231q2133q2131

q211q143q141q132q1312

p1122p121p123p132p1332

p252p243p241p223p163p161p14p12

q121q141q143q221q232q241q243q312q321q323q332q34q361q372

q12

q342q333q331q313q311q2232q2133q2131q2113q2111

p12p132p211p213p222p23p242

q243q241q232q223q221

q143q141

q134q132

q121q1112p12

p141p143

p152p154

q252q243

q241q232

q2132

q212q12

p12

p132

q22

p12

MYC (8q2421)

t(814)(q24q32)t(822)(q24q11) t(28)(p12q24)

48 Mbp

51 Mbp

RB1

MIR15-AMIR16-1


Type I

Type II

Chromosomalregion



Prog

nosis

Prog

nosis

13q142


































5 Clonal Evolution











Acknowledgments


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















P27 (12p131)

MYF6 (12q2131)

CDK4 (12q141)MDM2 (12q15)

HIP1R (12q2431)

TP53 (17p131)17

MYCN (2p243)

REL (2p161)BCL11A (2p161)

SF3B1 (2q331)

2 2p25

2p13

17p13

17p11

Poor

Varia

ble

Goo

dIn

term

edia

tePo

or

11q221

11q231

BIRC3 (11q222)

ATM (11q223)

11 12

9

NOTCH1 (9q343)

t(1418)(q32q24)t(1419)(q32q24)Others

14

IGH (14q32)

8 13

TNFRSF10AB (8p213)

p232

p22p212

q1122q121q123q132q2111q2113q213q222q231q233q2412q2421q2423

q333q331q322q313q311

q222q2133

q2131q211

q1412q133q131q122q1212

q132q211q213q222q231q233q242

q311q313q3212

q322

q12

q2432q2423q2421q233q231q2133q2131

q211q143q141q132q1312

p1122p121p123p132p1332

p252p243p241p223p163p161p14p12

q121q141q143q221q232q241q243q312q321q323q332q34q361q372

q12

q342q333q331q313q311q2232q2133q2131q2113q2111

p12p132p211p213p222p23p242

q243q241q232q223q221

q143q141

q134q132

q121q1112p12

p141p143

p152p154

q252q243

q241q232

q2132

q212q12

p12

p132

q22

p12

MYC (8q2421)

t(814)(q24q32)t(822)(q24q11) t(28)(p12q24)

48 Mbp

51 Mbp

RB1

MIR15-AMIR16-1


Type I

Type II

Chromosomalregion



Prog

nosis

Prog

nosis

13q142


































5 Clonal Evolution











Acknowledgments


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































5 Clonal Evolution











Acknowledgments


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Acknowledgments


References





































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article genetic abnormalities in chronic lymphocytic...

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