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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 12q13 was cryptic (Panagopoulos et al., 2006). The other ALL case also had a trisomy 16 and a trisomy 21. The t(12;12)(p13;q13) was an additional anomaly to a t(11;19)(q23;p13.1) in the treatment related AML-M2 case. The apparently de novo AML-M2 case have had a del(7q) prior to the t(12;12). The M6-AML case had a del(5q), a del(20q) and a complex karyotype. Clinics Out of 5 cases herein taken into account, 3 cases presented with a rearranged ETV6 gene, and only one of these cases was identified to carry an ETV6/BAZ2A hybrid gene. This case was a 3-year-old girl with a preB acute lymphoblastic leukaemia (CD10+ ALL). She achieved complete remission (CR), and was remaining in CR 18 months after diagnosis (Panagopoulos et al., 2006). The 2 other ETV6+ cases were acute myeloid leukemia (AML) cases: a 77-year-old male patient with AMLM2. Complete remission was achieved; he relapsed and died of sepsis (Saitoh et al., 2002); and a 46-year-old female patient with treatment related AML-M2, developping years after treatment for breast cancer; the patient has been in continuous relapse for the last 4 months after onset of AML (Manola et al., 2008). The 2 last cases were: a 4-years-old boy with ALL; the patient was alive 27 months after diagnosis (Heerema et al., 1985); and a 62-years-old female patient with AML-M6 with a 2 months survival (Mazzella et al., 1998). Altogether, this makes 2 pediatric ALL cases, and 3 adult AML cases, with perhaps different prognoses between the two categories. Excluded here is a case of refractory anemia with excess blasts with HMGA2 involvement (Odero et al., 2005), although the 4 above mentionned cases where BAZ2A was not studied may also have had a HMGA2 rearrangement. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9) Genes involved and proteins ETV6 Location 12p13.2 Protein ETV6 is a transcriptional repressor belonging to the ETS family. ETV6 displays a HLH domain (also referred to as the pointed (PNT) or sterile alpha motif (SAM) domain), responsible for hetero- and homodimerization, a central domain involved in the recruitment of a repression complex including NCOR2 and SIN3, and an ETS domain, responsible for sequence specific DNA-binding to DNA-responsive elements. Repression involves the recruitment of co-repressor complexes and HDACs or the recruitment of L3MBTL-containing polycomb group-complexes that facilitate repression by chromatin remodeling. ETV6 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 essential regulator of stem cells, important in vitelline angiogenesis and in bone marrow hematopoiesis. ETV6 expands erythroid precursors and stimulates hemoglobin synthesis (Knezevich, 2005; EguchiIshimae et al., 2009; Meester-Smoor et al., 2011). References Heerema NA, Palmer CG, Baehner RL. Karyotypic and clinical findings in a consecutive series of children with acute lymphocytic leukemia. Cancer Genet Cytogenet. 1985 Jun;17(2):165-79 Mazzella FM, Kowal-Vern A, Shrit MA, Wibowo AL, Rector JT, Cotelingam JD, Collier J, Mikhael A, Cualing H, Schumacher HR. Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis. Am J Clin Pathol. 1998 Nov;110(5):590-8 BAZ2A Location 12q13.3 Protein BAZ2A comprises from N-term to C-term a MBD (methyl-CpG-binding) domain, 2 AT hooks, a DDT (DNA binding homeobox and different transcription factors), 2 AT hooks again, a PHD-type zinc finger, and a bromo domain. The bromo domain and the PHDtype zinc finger recognize and bind histone H4. These 2 domains play a central role in the recruitment of chromatin silencing proteins such as DNMT1, DNMT3B and HDAC1 (Swiss-Prot). The NoRC (nucleolar remodeling complex) comprises BAZ2A and SMARCA5. A mechanism for silencing active ribosomal RNA (rRNA) genes is the recruitment by TTF1 (transcription termination factor-1) of NoRC to the promoter of rRNAs in the nucleolus. PARP1, component of the machinery that establishes and maintains silent rDNA chromatin during cell division, binds to BAZ2A (Guetg et al., 2012). BAZ2A is upregulated in patients with chronic lymphocytic leukemia (Hanlon et al., 2009). Saitoh T, Nakamura T, Inoue M, Hatta Y, Yamazaki T, Takeuchi J, Sawada U, Horie T. Different clones of t(1;12)/t(12;12) involving the ETV6 gene in a case of acute myeloid leukemia. Cancer Genet Cytogenet. 2002 Sep;137(2):138-41 Odero MD, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos JL, Andrieux J, Laï JL, Calasanz MJ, Cross NC. Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies. Leukemia. 2005 Feb;19(2):245-52 Knezevich S.. ETV6 (ETS variant gene 6 (TEL oncogene)). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL: http://AtlasGeneticsOncology.org/Genes/ETV6ID38.html Panagopoulos I, Strombeck B, Isaksson M, Heldrup J, Olofsson T, Johansson B.. Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement. Br J Haematol. 2006 May;133(3):270-5. Manola KN, Georgakakos VN, Margaritis D, Stavropoulou C, Panos C, Kotsianidis I, Pantelias GE, Sambani C.. Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer. Cancer Genet Cytogenet. 2008 Jan 1;180(1):37-42. Result of the chromosomal anomaly Eguchi-Ishimae M, Eguchi M, Maki K, Porcher C, Shimizu R, Yamamoto M, Mitani K.. Leukemia-related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis. Cancer Sci. 2009 Apr;100(4):689-97. doi: 10.1111/j.1349-7006.2009.01097.x. Epub 2009 Mar 11. Hybrid gene Transcript Transcript consisting of exons 1 and 2 of ETV6 and a sequence from intron 1 of BAZ2A. This transcript is not expected to produce any chimeric protein. Hanlon K, Rudin CE, Harries LW.. Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL). PLoS One. 2009 Sep 25;4(9):e7169. doi: 10.1371/journal.pone.0007169. Meester-Smoor MA, Janssen MJ, ter Haar WM, van Wely KH, Aarnoudse AJ, van Oord G, van Tilburg GB, Zwarthoff EC.. The ETS family member TEL binds to nuclear receptors RAR and RXR and represses gene activation. PLoS One. 2011;6(9):e23620. doi: 10.1371/journal.pone.0023620. Epub 2011 Sep 16. Fusion protein Description The transcript may encode a truncated form of ETV6, containing the first 54 amino acids (aa) of ETV6, followed by 16 aa from the 3' fusion sequence. Oncogenesis The production of a truncated form of ETV6 is reminiscent of ETV6 fusions with MDS2, FCHO2, PER1, and STL, according to Panagopoulos et al., 2006. BAZ2A may also be deregulated. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9) Guetg C, Scheifele F, Rosenthal F, Hottiger MO, Santoro R.. Inheritance of silent rDNA chromatin is mediated by PARP1 via noncoding RNA. Mol Cell. 2012 Mar 30;45(6):790-800. doi: 10.1016/j.molcel.2012.01.024. Epub 2012 Mar 8. This article should be referenced as such: Huret JL. t(12;12)(p13;q13) ETV6/BAZ2A. Atlas Cytogenet Oncol Haematol. 2013; 17(9):640-641. 641 Genet