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Leukaemia Section Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST -CNRS OPEN ACCESS JOURNAL Leukaemia Section Short Communication t(12;12)(p13;q13) ETV6/BAZ2A Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: March 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1212p13q13ID1452.html DOI: 10.4267/2042/51429 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Cytogenetics Disease Cytogenetics morphological Acute leukemias In the case where ETV6/BAZ2A rearrangement was ascertained, the rearrangement between 12p13 and Clinics 12q13 was cryptic (Panagopoulos et al., 2006). The Out of 5 cases herein taken into account, 3 cases other ALL case also had a trisomy 16 and a trisomy 21. presented with a rearranged ETV6 gene, and only one The t(12;12)(p13;q13) was an additional anomaly to a of these cases was identified to carry an ETV6/BAZ2A t(11;19)(q23;p13.1) in the treatment related AML-M2 hybrid gene. This case was a 3-year-old girl with a pre- case. B acute lymphoblastic leukaemia (CD10+ ALL). She The apparently de novo AML-M2 case have had a achieved complete remission (CR), and was remaining del(7q) prior to the t(12;12). in CR 18 months after diagnosis (Panagopoulos et al., The M6-AML case had a del(5q), a del(20q) and a 2006). complex karyotype. The 2 other ETV6+ cases were acute myeloid leukemia (AML) cases: a 77-year-old male patient with AML- Genes involved and proteins M2. Complete remission was achieved; he relapsed and died of sepsis (Saitoh et al., 2002); and a 46-year-old ETV6 female patient with treatment related AML-M2, Location developping years after treatment for breast cancer; the 12p13.2 patient has been in continuous relapse for the last 4 Protein months after onset of AML (Manola et al., 2008). ETV6 is a transcriptional repressor belonging to the The 2 last cases were: a 4-years-old boy with ALL; the ETS family. ETV6 displays a HLH domain (also patient was alive 27 months after diagnosis (Heerema referred to as the pointed (PNT) or sterile alpha motif et al., 1985); and a 62-years-old female patient with (SAM) domain), responsible for hetero- and AML-M6 with a 2 months survival (Mazzella et al., homodimerization, a central domain involved in the 1998). recruitment of a repression complex including NCOR2 Altogether, this makes 2 pediatric ALL cases, and 3 and SIN3, and an ETS domain, responsible for adult AML cases, with perhaps different prognoses sequence specific DNA-binding to DNA-responsive between the two categories. Excluded here is a case of elements. refractory anemia with excess blasts with HMGA2 Repression involves the recruitment of co-repressor involvement (Odero et al., 2005), although the 4 above complexes and HDACs or the recruitment of mentionned cases where BAZ2A was not studied may L3MBTL-containing polycomb group-complexes that also have had a HMGA2 rearrangement. facilitate repression by chromatin remodeling. ETV6 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9) 640 t(12;12)(p13;q13) ETV6/BAZ2A Huret JL binds to nuclear receptors RARA and RXRA and represses gene activation. ETV6 is as a selective and References essential regulator of stem cells, important in vitelline Heerema NA, Palmer CG, Baehner RL. Karyotypic and clinical angiogenesis and in bone marrow hematopoiesis. ETV6 findings in a consecutive series of children with acute lymphocytic leukemia. Cancer Genet Cytogenet. 1985 expands erythroid precursors and stimulates Jun;17(2):165-79 hemoglobin synthesis (Knezevich, 2005; Eguchi- Ishimae et al., 2009; Meester-Smoor et al., 2011). Mazzella FM, Kowal-Vern A, Shrit MA, Wibowo AL, Rector JT, Cotelingam JD, Collier J, Mikhael A, Cualing H, Schumacher BAZ2A HR. Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and Location prognosis. Am J Clin Pathol. 1998 Nov;110(5):590-8 12q13.3 Saitoh T, Nakamura T, Inoue M, Hatta Y, Yamazaki T, Protein Takeuchi J, Sawada U, Horie T. Different clones of BAZ2A comprises from N-term to C-term a MBD t(1;12)/t(12;12) involving the ETV6 gene in a case of acute (methyl-CpG-binding) domain, 2 AT hooks, a DDT myeloid leukemia. Cancer Genet Cytogenet. 2002 Sep;137(2):138-41 (DNA binding homeobox and different transcription factors), 2 AT hooks again, a PHD-type zinc finger, Odero MD, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos and a bromo domain. The bromo domain and the PHD- JL, Andrieux J, Laï JL, Calasanz MJ, Cross NC. Disruption and aberrant expression of HMGA2 as a consequence of diverse type zinc finger recognize and bind histone H4. These 2 chromosomal translocations in myeloid malignancies. domains play a central role in the recruitment of Leukemia. 2005 Feb;19(2):245-52 chromatin silencing proteins such as DNMT1, Knezevich S.. ETV6 (ETS variant gene 6 (TEL oncogene)). DNMT3B and HDAC1 (Swiss-Prot). The NoRC Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL: (nucleolar remodeling complex) comprises BAZ2A and http://AtlasGeneticsOncology.org/Genes/ETV6ID38.html SMARCA5. A mechanism for silencing active Panagopoulos I, Strombeck B, Isaksson M, Heldrup J, ribosomal RNA (rRNA) genes is the recruitment by Olofsson T, Johansson B.. Fusion of ETV6 with an intronic TTF1 (transcription termination factor-1) of NoRC to sequence of the BAZ2A gene in a paediatric pre-B acute the promoter of rRNAs in the nucleolus. PARP1, lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement. Br J Haematol. 2006 May;133(3):270-5. component of the machinery that establishes and maintains silent rDNA chromatin during cell division, Manola KN, Georgakakos VN, Margaritis D, Stavropoulou C, binds to BAZ2A (Guetg et al., 2012). BAZ2A is up- Panos C, Kotsianidis I, Pantelias GE, Sambani C.. Disruption of the ETV6 gene as a consequence of a rare translocation regulated in patients with chronic lymphocytic (12;12)(p13;q13) in treatment-induced acute myeloid leukemia leukemia (Hanlon et al., 2009). after breast cancer. Cancer Genet Cytogenet. 2008 Jan 1;180(1):37-42. Result of the chromosomal Eguchi-Ishimae M, Eguchi M, Maki K, Porcher C, Shimizu R, Yamamoto M, Mitani K.. Leukemia-related transcription factor anomaly TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis. Cancer Sci. 2009 Apr;100(4):689-97. Hybrid gene doi: 10.1111/j.1349-7006.2009.01097.x. Epub 2009 Mar 11. Transcript Hanlon K, Rudin CE, Harries LW.. Investigating the targets of Transcript consisting of exons 1 and 2 of ETV6 and a MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL). PLoS One. 2009 Sep 25;4(9):e7169. doi: sequence from intron 1 of BAZ2A. This transcript is 10.1371/journal.pone.0007169. not expected to produce any chimeric protein. Meester-Smoor MA, Janssen MJ, ter Haar WM, van Wely KH, Fusion protein Aarnoudse AJ, van Oord G, van Tilburg GB, Zwarthoff EC.. The ETS family member TEL binds to nuclear receptors RAR Description and RXR and represses gene activation. PLoS One. The transcript may encode a truncated form of ETV6, 2011;6(9):e23620. doi: 10.1371/journal.pone.0023620. Epub containing the first 54 amino acids (aa) of ETV6, 2011 Sep 16. followed by 16 aa from the 3' fusion sequence. Guetg C, Scheifele F, Rosenthal F, Hottiger MO, Santoro R.. Oncogenesis Inheritance of silent rDNA chromatin is mediated by PARP1 via The production of a truncated form of ETV6 is noncoding RNA. Mol Cell. 2012 Mar 30;45(6):790-800. doi: 10.1016/j.molcel.2012.01.024. Epub 2012 Mar 8. reminiscent of ETV6 fusions with MDS2, FCHO2, PER1, and STL, according to Panagopoulos et al., This article should be referenced as such: 2006. BAZ2A may also be deregulated. Huret JL. t(12;12)(p13;q13) ETV6/BAZ2A. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9):640-641. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9) 641 .
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