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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Leukaemia Section Short Communication t(9;17)(p13;p12) PAX5/NCOR1 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: July 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0917p13p12ID1597.html DOI: 10.4267/2042/56416 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 activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-toDJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011). Abstract Review on t(9;17)(p13;p12) PAX5/NCOR1, with data on clinics, and the genes implicated. Clinics and pathology Disease B-cell acute lymphoblastic leukemia (B-ALL) Epidemiology One case to date, a 2-year-old boy with a CD10+ (B-II, common) ALL (Coyaud et al., 2010). NCOR1 Prognosis Location 17p12 Protein 2440 amino acids; from N-term to C-term, NCOR1 contains: a repression domains (responsible for the repressive activity of the corepressor) (aa 1-312); a poly-Gln stretch (aa 58-64), two coiled coil domains (aa 174-216 and aa 299-328); a SANT (Swi3, Ada2, NCoR1, TFIIB) domain (deacetylase activation domain (DAD)) (aa 435-486); a coiled coil domain (aa 501-557); a poly-Ala stretch (aa 593-603); a Pro-rich stretch (aa 607-617); a SANT domain (histone interaction domain (HID)) (aa 623674); a poly-Pro stretch (aa 1032-1035); a poly-Ala stretch (aa 1707-1712); a CoRNR box motif (Leux-x-Leu-Leu motifs) (aa 1933-1937); a poly-Ser stretch (aa 1952-1963); a nuclear receptorinteracting domain ID1 (aa 2032-2115); a CoRNR box motif (aa 2055-2059); another nuclear receptorinteracting domain ID2 (aa 2212-2273); and a CoRNR box motif (aa 2263-2267). No data. Genes involved and proteins PAX5 Location 9p13.2 Protein 391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) 225 t(9;17)(p13;p12) PAX5/NCOR1 Huret JL PAX5-NCOR1 fusion protein. NCOR1 and NCOR2 (12q24, also called SMRT) are transcriptional corepressors that associate with nuclear hormone receptors (thyroid hormone receptors and retinoic acid receptors) in the absence of ligand. Thyroid hormone receptors interact specifically with the ID3 and ID2 domains of NCOR1 (ID domains contain an isoleucine-rich domain, named the CoRNR box, this CoRNR box is required for nuclear hormone receptors interaction). SANT-like domains promote histone deacetylation. Repression is mediated by formation of a large corepressor complex that contains SIN3A/B (15q24 and 19p13), recruiting multiple histone deacetylase enzymes such as HDAC1 (1p35), HDAC2 (6q21), HDAC3 (5q31), HDAC4 (2q37), HDAC7 (12q13), and SIRT1 (10q21), resulting in the formation of repressive chromatin structures. This complex associates with the thyroid hormone receptor and the retinoic acid receptor. NCOR1 and NCOR2 also interact with many other transcription factors including: BCL6 (3q27), RUNX1T1 (8q21, also called ETO), SPEN (1p36, also called SHARP), ZBTB33 (Xq24), HEXIM1 (17q21), TBL1XR1 (3q26), MEF2C (5q14), CNOT2 (12q15), and RBJP (4p15), Jun proteins and the NFKB pathway (Li et al., 1997; Watson et al., 2012; Mottis et al., 2013). octapeptide of PAX5 (201 aa), and most the ID2 region (containing the CoRNR box motif) of NCOR1 (214 aa). Result of the chromosomal anomaly Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a master regulator of B cell development and leukemogenesis. Adv Immunol. 2011;111:179-206 Hybrid gene Watson PJ, Fairall L, Schwabe JW. Nuclear hormone receptor co-repressors: structure and function. Mol Cell Endocrinol. 2012 Jan 30;348(2):440-9 References Li H, Leo C, Schroen DJ, Chen JD. Characterization of receptor interaction and transcriptional repression by the corepressor SMRT. Mol Endocrinol. 1997 Dec;11(13):2025-37 Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004 Feb 15;18(4):411-22 Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cellspecific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):85361 Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD. Transcription factor Pax5 (BSAP) transactivates the RAGmediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol. 2006 Jun;7(6):616-24 Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 May;8(5):463-70 Coyaud E, Struski S, Prade N, Familiades J et al.. Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study. Blood. 2010 Apr 15;115(15):3089-97 Description Fusion of PAX5 exon 5 to NCOR1 exon 43. Mottis A, Mouchiroud L, Auwerx J. Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev. 2013 Apr 15;27(8):819-35 Fusion protein Description 415 amino acids. The predicted fusion protein contains the DNA binding paired domain, and the Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) This article should be referenced as such: Huret JL. t(9;17)(p13;p12) PAX5/NCOR1. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3):225-226. 226