Download Leukaemia Section t(9;17)(p13;p12) PAX5/NCOR1 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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