molecular aspect of cml 2014 pptok
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dr. Irza Wahid, SpPD-KHOM
Curriculum Vitae :T.TGL-L : Padang, 23 November 19!
"abatan #e$arang :
- %e&ala #ubbagian 'ematologi
(n$ologi )edi$ *ag. +P % nand
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MOLECULAR ASPECT OF PATHOGENESISAND MANAGEMENT OF
CHRONIC MYELOID LEUKEMIA
IRZA WAHID
SUBDIVISION OF HEMATOLO! " MEDI#AL ON#OLO!,DEPARTEMENT OF INTERNAL MEDI#INE
ENERAL HOSPITAL OF M D$AMILFA#ULT! OF MEDI#INE, ANDALAS UNIVERSIT!, PADAN
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INTRODUCTION
L%&'a%(ia a))*&+ *r /01 * a22 )a+)%r i+ h&(a+3-0
4 I+)id%+)%5 6-37 )a% p%r 377,777 p*p&2ai*+ #ML a))*&+ *r 361-871 * a22 ad&2 2%&'a%(ia9,6
4 I+)id%+)%5 3-8 )a% p%r 377,777 p*p&2ai*+9,:
4 O))&r 2i;h2< (*r% r%=&%+2< i+ (%+ ha+ >*(%+ ?3.9-8.853@
M%dia+ pai%+ a;% a dia;+*i5 66-:7 +
* % )a&%d < a+ &+d%r2>-d%p.iar).r. 8. #a+)%r R%%ar)h UK. AGai2a2% a5
hp5>>>.)a+)%rr%%ar)h&'.*r;a*&)a+)%raii)i+)id%+)%. 0. F%r2a< $ % a2. EU#AN. AGai2a2% a5 hp5>>>-
d%p.iar).r%&)a+%&)a+.h(. 9. Dr&'%r B$. Cancer Cell . 87783503-0:. 6. r%%+2%% RT % a2. CA Cancer J Clin. 877363536-0:. :.
Ri% LA % a2. SEER #a+)%r Saii) R%Gi%>, 3C6-8773. AGai2a2% a5 hp5%%r.)a+)%r.;*G)r3C6J8773. . #*r% $.
Hematol Oncol Clin North Am. 8779356:C-69. . N*>%22 P# % a2. J Natl Cancer Inst. 3C:3853730-3706.
MOLECUL
ASPECT
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CA Cancer J Clin 2011;61:212-236. VC 2011 American Cancer Scie!".
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S!r#$!#r Sel
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%rmal &ar"!"'e
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(a)e Pem*ela+an Sel
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DNA -------------> RNA ------------> PROTEIN
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Haematopoiesis: !oo" Ce!! Li#ea$es
Dia;ra( r%pr*d&)%d >ih p%r(ii*+ r*( W.H.
Fr%%(a+ #*(pa+ !*r', N!, USA.
H*ra+d AV % a2. Essential Hematology. 9h %d.
O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.
Haematopoiesis: p%o&ess '()*i&* '!oo"-&e!! !i#ea$es a%e
p%o"+&e" '( 'o#e ma%%o)
,Cs )*ite '!oo" &e!!s. o%
!e+/o&(tes0 s+'"i1i"e" i#to " M(e!oi" !i#ea$es " L(mp*oi" !i#ea$es
G%a#+!o&(tes massi1e!( e2pa#"e"
i# CML
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Stem Ce!!s a#" Haematopoieti& Di33e%e#tiatio#
Dia;ra( r%pr*d&)%d >ih p%r(ii*+ r*( Pr*. Dr. A)hi( L%&z, Ma D%2r)' #%+%r *r M*2%)&2ar M%di)i+%, B%r2i+.
H*ra+d AV % a2. Essential Hematology. 9h %d. O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.
Haematopoieti& stem &e!!sHaematopoieti& stem &e!!s&apa'!e o3 &apa'!e o3
" Se!3-%e#e)a!Se!3-%e#e)a!
" Di33e%e#tiatio#Di33e%e#tiatio#
Di33e%e#tiatio# a#" p%o!i3e%atio#Di33e%e#tiatio# a#" p%o!i3e%atio#
&o#t%o!!e" '( mo!e&+!a% si$#a!s&o#t%o!!e" '( mo!e&+!a% si$#a!s " Co#ta&t )it* st%oma! &e!!s i#Co#ta&t )it* st%oma! &e!!s i#
'o#e ma%%o)'o#e ma%%o)
" G%o)t* 3a&to%sG%o)t* 3a&to%s
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Si$#a! T%a#s"+&tio#
Ad%i AA % a2. J Clin Oncol. 877680560:-6970. R%pr*d&)%d >ih p%r(ii*+.
Prli,era)i
i,eren)ia
A''!)i)
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Pat*o$e#esis
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Ge#eti&s a#" Ce!!+!a% P%o!i3e%atio#
N%*p2ai) ra+*r(ai*+i+iia%d <
4 P*i+ (&ai*+
4 #hr*(**(a2 2*,
d&p2i)ai*+, *r
i+appr*pria%
r%)*(i+ai*+4 L* * %pr%i*+ * a
;%+% ha i+hii )%22
pr*2i%rai*+ *r pr*(*%
ap*p*i
Dia;ra( )*&r%< * Nai*+a2 #a+)%r I+i&%, USA.
H*ra+d AV % a2. Essential Hematology. 9h %d. O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.
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#ML4 Pr*2i%raiG% di*rd%r * h%(a*p*i%i) %( )%22
Phi2ad%2phia ?Ph@ )hr*(**(%
4 U+i=&% )hr*(**(a2 a+*r(a2i<
B#R-ABL
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4 5 6 7 8
9 ; < 4= 44 45
46 47 48 49 4 4;
4< 5= 54 55 Y
P* C*%omosomeCytogenetic Abnormality of CML
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?C88@?=09=33@4 ra+2*)ai*+4 = 2*+; ar( * )hr*(**(%
P* C*%omosomeReciprocal Translocation
I(a;% r*(5
Ka2ida M, Ka+aria+ H, Ta2paz M. JAMA. 87738:?@5C6-C
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CR ? AL O#&op%otei#
4Ph )hr*(**(% >a di)*G%r%d i+ 3C:7 < H&+;%r*rd a+d N*>%22.
4T* % h% r%&2 * )hr*(**(a2 ra+2*)ai*+ ?R*>2%a< ;r*>h, &rGiGa2, ra+*r(ai*+
4B< MAPK, $NK, SAPK, NF-', STAT, SR#, a(i2< 'i+a%
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P* C*%omosome
P%e1a!e#&e o3t*e P*i!a"e!p*ia &*%omosome
T(pe o3 !e+/emia P*@ patie#ts 0
CML
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P* C*%omosomebcr-abl Fusion Gene
I(a;% r*(5
Ka2ida M, Ka+aria+ H, Ta2paz M. JAMA. 87738:?@5C6-C
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CR-AL P%otei#Disrupts Signal Transduction Pat!ays
Prolonged survival
Increased migration from
bone marrow
Uncontrolledproliferation
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ian)i)
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Pe%ip*e%a! !oo" Smea%
No%ma! C*%o#i& p*ase CML
I#&%ease" ,Cs
Mat+%e
Immat+%e
Note:
I#&%ease" 'asop*i!i&
$%a#+!o&(tes 'asop*i!
i# pa%ti&+!a%
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C!i#i&a! Co+%sePases of "ntreated CML
Disease p%o$%essio#
C*%o#i& p*ase
7?9 (ea%s
B;8 o3 patie#ts
p%ese#t i# t*is
p*ase
48 ma%%o) o%
pe%ip*e%a! '!asts
Up to 4 (ea%
,ei$*t !oss. 3e1e%.
'o#e pai#
48?5= ma%%o) o%
pe%ip*e%a! '!asts
A 3e) )ee/s to 9
mo#t*s
Poo% p%o$#osis %api"!(
3ata!
> 5= ma%%o) o%
pe%ip*e%a! '!asts
A&&e!e%ate" p*ase !ast &%isis
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C!i#i&a! C%ite%ia a#" P*ases o3 P*@ CML
Pa%amete% C*%o#i&p*ase A&&e!e%ate" p*ase !ast &%isis
,C &o+#t 5= 2 4=< &e!!sL
!asts 48 48?6= 5=?6=
asop*i!s 5= 5=
P!ate!ets o% #o%ma! o%
Ma%%o) &e!!+!a%it(
C(to$e#eti&s P*@ P*@ P*@
bcr-abl @ @ @
WB# >hi% 2**d )%22
PhQ Ph )hr*(**(%"p*iiG%
C(to$e#eti&
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C(to$e#eti&Fluorescence #n Situ $ybridi%ation &F#S$'
Courtesy of Charles L. Sawyers, M, !CLA.
M%h*d *r d%%)i+; "cr#a"l *+ h% Ph )hr*(**(%
bcr-abl
La'e!e" bcr-abl $e#e
La'e!e" DNA p%o'e
3!+o%es&e#t0
bcr-abl $e#e
Sepa%ate DNA st%a#"s
a#" a"" !a'e!e" p%o'e
N+&!ea% DNA
M ! !
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Mo!e&+!a%Polymerase Cain Reaction
RT-P#R d%%) "cr#a"l ra+)rip
R-P#R =&a+ii% "cr#a"l ra+)rip
4 B% i+d% * (i+i(a2 r%id&a2 di%a% ?MRD@4 R%p*ri+; Gari% %>%%+ 2a*ra*ri%
4 Sa+dardiz%d I+%r+ai*+a2 S)a2% ?IS@ i+
d%G%2*p(%+
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T+era'"
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Hemato!o$i&%espo#se
C(to$e#eti&%espo#se
Mo!e&+!a%%espo#se
Comp!ete '!oo"&o+#ts CCs0
Ka%(ot(pi#$ Re1e%se t%a#s&%iptasepo!(me%ase &*ai# %ea&tio#RT-PCR0
F!+o%es&e#t i# sit+*('%i"iJatio# FISH0
Rea!-time +a#titati1epo!(me%ase &*ai# %ea&tio# R-PCR0
%rmal A*)ence A*)ence
Mo#ito%i#$ T*e%ape+ti& Respo#se
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'&%-a'! M+tatio#a! A#a!(sis
M&ai*+ i+ h% 'i+a% d*(ai+ ?KD@ * "cr#a"l (a< % a*)ia%d >ih
r%ia+)% * 2iG%)
4 Pai%+ >ih di%a% pr*;r%i*+ *+ 2iG%) >h* haG% p**r
)h* haG%
i;+ii)a+ i+)r%a% i+ h% "cr#a"l 2%G%2, h*&2d % ar;%%d *r
(&ai*+ &di%
4 M&ai*+ d%%)%d i+ *G%r C7 di%r%+ p*ii*+ i+ "cr#a"l
4 T036I (&ai*+ a*)ia%d >ih p**r pr*;+*i
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D%+$ Resista#&e
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S+mma%( a#" Co#&!+sio#s
M*2%)&2ar ap%) i G%r< i(p*ra+ i+ pah*;%+%i, dia;+*i a+d h%rap< * #
Ph )hr*(**(% a+d &i*+ * B#R-ABL ;%+% a a ai) (%)ha+i( * #ML
4 Tra+2*)ai*+ * 8 %;(%+ " ?C88@ " r%&2i+; i+ a+ a+*r(a2 h
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T H A N K Y O U