Leukaemia Section Short Communication

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) 227

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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t(11;14)(p15;q22) AP2A2/NID2 Nathalie Douet-Guilbert, Etienne De Braekeleer, Corinne Tous, Nadia Guéganic, Audrey Basinko, Marie-Josée Le Bris, Frédéric Morel, Marc De Braekeleer

Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France (NDG, EDB, CT, NG, AB, MJLB, FM, MDB)

Published in Atlas Database: August 2014

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1114p15q22ID1677.html DOI: 10.4267/2042/56417

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review on t(11;14)(p15;q22) AP2A2/NID2, with data on clinics, and the genes implicated.

Clinics and pathology Disease Myelodysplastic syndrome

Epidemiology A single case of Philadelphia chromosome-positive chronic myeloid leukemia with t(11;14)(p15;q22) following allogeneic stem cell transplantation in a 32 year-old male is reported in the literature. The translocation is associated with a complex karyotype. No molecular characterization was performed (Karrman et al., 2007).

Clinics A 71-year-old woman seen because of macrocytic anemia without etiology.

Cytology Bone marrow aspirate showing dysgranulopoiesis and dyserythropoiesis. Presence of ring sideroblasts (24%) signing a refractory anemia with ring sideroblasts (RARS).

Evolution Patient alive two years later.

Cytogenetics The t(11;14)(p15;q22) involves two genes, the AP2A2 and NID2 genes, that have never been shown to form a fusion gene.

RHG banding showing chromosomes 11 and 14 and the derivatives der(11) and der(14).

Cytogenetics morphological t(11;14)(p15;q22) is identified by banding cytogenetics.

Cytogenetics molecular To determine the position of the breakpoints on chromosomes 11 and 14, BACs located in the bands of interest were used as probes in FISH experiments. Analysis with RP11-51L17 showed that one signal hybridized to the normal chromosome 11, and the other hybridized to the der(14). Analysis with RP11-963I11 showed that one signal hybridized to the normal chromosome 14, and the other split and hybridized to both der(11) and der(14). Co-hybridization with both BAC clones showed one fusion signal.

t(11;14)(p15;q22) AP2A2/NID2 Douet-Guilbert N, et al.

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FISH with BACs RP11-51L17 (spectrum orange, located in 11p15 and containing AP2A2) and RP11-963I11 (spectrum green, located in 14q22 and containing NID2) showing co-hybridization. During the FISH analyses with BAC clones on chromosome 11, we found that RP11-51L17 was translocated to der(14) and RP11-613G2 was deleted. RP11-51L17 is mapped between positions 774448 and 952590 and RP11-613G2 between positions 952562 and 1128625. The AP2A2 is mapped from positions 925809 to 1012245. The region of overlap between both BAC clones is included between exons 1 and 2 of AP2A2 (UCSC Genome Browser on Human Feb. 2009 (GRCh37/hg19) Assembly). Deletion of RP11-613G2 explains why only one fusion signal was observed. RP11-51L17 contains the AP2A2 (adaptor-related protein complex 2, alpha 2 subunit) gene and RP11-963I11 the NID2 (Nidogen 2) gene.

Genes involved and proteins AP2A2 Location 11p15.5

DNA/RNA The AP2A2 gene contains 22 coding exons, spanning 86.4 kb. Three alternative transcripts are known (Nagase et al., 1998).

Protein The protein has 939 amino acids. It is a component of the adaptor protein complex 2 (AP-2) (Ohno, 2006). AP-2 is involved in clathrin-dependent endocytosis in which proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated

t(11;14)(p15;q22) AP2A2/NID2 Douet-Guilbert N, et al.

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vesicles) which are destined for fusion with the early endosome. AP-2 is involved in a wide range of biological processes, notably signalling mediated by Notch, Wnt, EGF and transforming growth factor-b (TGF-b) superfamily members (Foerster et al., 2013; Mizutani et al., 2010; Sorkin and von Zastrow, 2009; Yao et al., 2002; Yu et al., 2007). AP2 was also found to be essential for thrombopoietin (Tpo)-stimulated clathrin-mediated internalization of its receptor c-Mpl. As Tpo promotes proliferation and survival of hematopoietic stem and progenitor cells and regulates megakaryocyte lineage differentiation and maturation, Tpo signal transduction has to be controlled (Hitchcock et al., 2008). More recently, a role for AP2A2 has been suggested in asymmetric cell division and self-renewal of hematopoietic stem and progenitor cells (Ting et al., 2012).

NID2 Location 14q22.1

Note NID2 expression was shown to be downregulated in tumor tissues from patients with hepatocellular carcinoma (Cheng et al., 2012). Aberrant methylation of NID2 promoter induces loss of gene expression in gastrointestinal tumors (stomach and colon) and in oral squamous cell carcinoma (Guerrero-Preston et al., 2011; Ulazzi et al., 2007).

DNA/RNA The NID2 gene contains 21 coding exons, spanning 64.4 kb (Kohfeldt et al., 1998).

Protein The NID2 gene encodes a 1375 amino acids protein that is a member of the nidogen family of basement membranes that control diverse cellular activities, including adhesion, migration, differentiation, gene expression and apoptosis. Its three dimensional structure consists of three globular domains connected by a flexible link and a rod (Kohfeldt et al., 1998). Disruption of the integrity of the basement membrane creates an invasion-permissive environment, often promoting cancer cell proliferation and invasion (metastasis) (Lester and McCarthy, 1992).

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This article should be referenced as such:

Douet-Guilbert N, De Braekeleer E, Tous C, Guéganic N, Basinko A, Le Bris MJ, Morel F, De Braekeleer M. t(11;14)(p15;q22) AP2A2/NID2. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3):227-229.