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t(9;17)(p13;p12) PAX5/NCOR1

Written2014-07Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1597

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).
Prognosis No data.

Genes involved and Proteins

Gene Name 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: 304-359); 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; 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-to-DJ 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).
Gene Name NCOR1
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 623-674); a poly-Pro stretch (aa 1032-1035); a poly-Ala stretch (aa 1707-1712); a CoRNR box motif (Leu-x-x-Leu-Leu motifs) (aa 1933-1937); a poly-Ser stretch (aa 1952-1963); a nuclear receptor-interacting domain ID1 (aa 2032-2115); a CoRNR box motif (aa 2055-2059); another nuclear receptor-interacting domain ID2 (aa 2212-2273); and a CoRNR box motif (aa 2263-2267).
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).

Result of the chromosomal anomaly

Hybrid gene
Description Fusion of PAX5 exon 5 to NCOR1 exon 43.
  
Fusion Protein
 
  PAX5-NCOR1 fusion protein.
Description 415 amino acids. The predicted fusion protein contains the DNA binding paired domain, and the octapeptide of PAX5 (201 aa), and most the ID2 region (containing the CoRNR box motif) of NCOR1 (214 aa).
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

Pax5: the guardian of B cell identity and function.
Cobaleda C, Schebesta A, Delogu A, Busslinger M.
Nat Immunol. 2007 May;8(5):463-70. (REVIEW)
PMID 17440452
 
Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study.
Coyaud E, Struski S, Prade N, Familiades J, Eichner R, Quelen C, Bousquet M, Mugneret F, Talmant P, Pages MP, Lefebvre C, Penther D, Lippert E, Nadal N, Taviaux S, Poppe B, Luquet I, Baranger L, Eclache V, Radford I, Barin C, Mozziconacci MJ, Lafage-Pochitaloff M, Antoine-Poirel H, Charrin C, Perot C, Terre C, Brousset P, Dastugue N, Broccardo C.
Blood. 2010 Apr 15;115(15):3089-97. doi: 10.1182/blood-2009-07-234229. Epub 2010 Feb 16.
PMID 20160164
 
Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene.
Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M.
Genes Dev. 2004 Feb 15;18(4):411-22.
PMID 15004008
 
B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5.
Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K.
Nat Immunol. 2004 Aug;5(8):853-61. Epub 2004 Jul 18.
PMID 15258579
 
Characterization of receptor interaction and transcriptional repression by the corepressor SMRT.
Li H, Leo C, Schroen DJ, Chen JD.
Mol Endocrinol. 1997 Dec;11(13):2025-37.
PMID 9415406
 
Pax5: a master regulator of B cell development and leukemogenesis.
Medvedovic J, Ebert A, Tagoh H, Busslinger M.
Adv Immunol. 2011;111:179-206. doi: 10.1016/B978-0-12-385991-4.00005-2. (REVIEW)
PMID 21970955
 
Emerging roles of the corepressors NCoR1 and SMRT in homeostasis.
Mottis A, Mouchiroud L, Auwerx J.
Genes Dev. 2013 Apr 15;27(8):819-35. doi: 10.1101/gad.214023.113. (REVIEW)
PMID 23630073
 
Nuclear hormone receptor co-repressors: structure and function.
Watson PJ, Fairall L, Schwabe JW.
Mol Cell Endocrinol. 2012 Jan 30;348(2):440-9. doi: 10.1016/j.mce.2011.08.033. Epub 2011 Sep 8. (REVIEW)
PMID 21925568
 
Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.
Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD.
Nat Immunol. 2006 Jun;7(6):616-24. Epub 2006 May 7.
PMID 16680144
 

Citation

This paper should be referenced as such :
JL Huret
t(9;17)(p13;p12) PAX5/NCOR1
Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):225-226.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0917p13p12ID1597.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(9;17)(p13;p12) PAX5/NCOR1

External links

Mitelman databaset(9;17)(p13;p12) [Case List]    t(9;17)(p13;p12) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaset(9;17)(p13;p12) PAX5/NCOR1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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