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t(9;22)(p13;q13) PAX5::BRD1

Written2014-03Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1562

Clinics and Pathology

Disease B-cell acute lymphoblastic leukemia (ALL)
Epidemiology Only one case to date, a 2-years old boy wit h a CD10+ ALL (Nebral et al., 2009).
Prognosis The patient was considered as at intermediate risk. He remains in complete remission 44 months after diagnosis.

Genes involved and Proteins

Gene NamePAX5 (paired box gene 5)
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 NameBRD1 (bromodomain containing 1)
Location 22q13.33
Protein 1058 amino acids (aa); from N-term to C-term, BRD1 contains a zinc finger PHD-type (aa 214-264); a bromo domain (aa 579-649) (recognizes acetylated lysine residues; prerequisite for protein-histone association and chromatin remodeling); a PWWP domain (aa 929-1012) (conserved Pro-Trp-Trp-Pro motif; binds histones independently of their acetylation, also binds DNA). Phosphoserines are at aa 128, 1052, and 1055, and N6-acetyllysine at aa 368, 516, 519, and 903. BN1 and BN2 (BRPF N-terminal conserved region 1 and 2) (aa 60-222) is the domain binding MOZ/MORF (Ullah et al., 2008). An enhancer of polycomb homology region (EPL1) (EPL1 protein are members of histone acetyltransferase complex) , which binds to ING5 and mediates association with MEAF6, is located from amino acids 540 and 640 (Ullah et al., 2008).
BRD1 is a subunit of the MOZ histone acetyl transferase (HAT) complex. The MOZ HAT functions is a multi-protein complex with BRD1, ING5 (inhibitor of growth 5, 2q37.3), and MEAF6 (MYST/Esa1-Associated Factor 6, 1p34.3). BRD1 links the MOZ catalytic subunit to the ING5 and MEAF6 subunits, and promotes MOZ HAT activity. The bromodomain of BRD1 acetylates lysine residues of histones H3, H4, H2A, and H2B (H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H2AK5ac). The PWWP domain of BRD1 is the binding module for trimethylation of Lys36 of histone H3 (H3K36me3) associated with the elongation phase of transcription (Vezzoli et al., 2010). There are different splice variants, which are induced differentially in different brain regions (Fryland et al., 2012). The variant BRPF2 may be a negative regulatory factor of the variant BRPF1. BRD1 is widely expressed in various tissues, the brain in particular (in the cell nucleus, perikaryal cytosol and proximal dendrites of the neurons), with high expression at early embryonic stages (Severinsen et al., 2006; Bjarkam et al., 2009). BRD1 has a central role during embryonic development through Moz-dependent histone acetylation, to maintain expression of Hox genes (Laue et al., 2008). BRD1 forms a novel HAT complex with KAT7 (HBO1, 17q21.33) and is required for transcriptional activation of erythroid developmental regulator genes (Mishima et al., 2011). BRD1 showed association with schizophrenia and bipolar affective disorder susceptibility (Bjarkam et al., 2009).

Result of the chromosomal anomaly

Hybrid gene
Description Fusion of PAX5 exon 5 to BRD1 non coding exon 1.
Fusion Protein
  PAX5/BRD1 fusion protein.
Description 1264 amino acids, according to the authors. The predicted fusion protein contains the DNA binding paired domain and octapeptide of PAX5 (201 aa), 4 amino acids, and the entire BRD1 (1058 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.


Further immunohistochemical characterization of BRD1 a new susceptibility gene for schizophrenia and bipolar affective disorder.
Bjarkam CR, Corydon TJ, Olsen IM, Pallesen J, Nyegaard M, Fryland T, Mors O, Borglum AD.
Brain Struct Funct. 2009 Dec;214(1):37-47. doi: 10.1007/s00429-009-0219-3. Epub 2009 Sep 10.
PMID 19763615
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
Electroconvulsive seizures regulates the Brd1 gene in the frontal cortex and hippocampus of the adult rat.
Fryland T, Elfving B, Christensen JH, Mors O, Wegener G, Borglum AD.
Neurosci Lett. 2012 May 10;516(1):110-3.
PMID 22675730
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
The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
Laue K, Daujat S, Crump JG, Plaster N, Roehl HH; Tubingen 2000 Screen Consortium, Kimmel CB, Schneider R, Hammerschmidt M.
Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160.
PMID 18469222
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
The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis.
Mishima Y, Miyagi S, Saraya A, Negishi M, Endoh M, Endo TA, Toyoda T, Shinga J, Katsumoto T, Chiba T, Yamaguchi N, Kitabayashi I, Koseki H, Iwama A.
Blood. 2011 Sep 1;118(9):2443-53. doi: 10.1182/blood-2011-01-331892. Epub 2011 Jul 13.
PMID 21753189
Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia.
Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA, Strehl S.
Leukemia. 2009 Jan;23(1):134-43. doi: 10.1038/leu.2008.306. Epub 2008 Nov 20.
PMID 19020546
Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder.
Severinsen JE, Bjarkam CR, Kiaer-Larsen S, Olsen IM, Nielsen MM, Blechingberg J, Nielsen AL, Holm IE, Foldager L, Young BD, Muir WJ, Blackwood DH, Corydon TJ, Mors O, Borglum AD.
Mol Psychiatry. 2006 Dec;11(12):1126-38. Epub 2006 Aug 22.
PMID 16924267
Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes.
Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Cote J, Yang XJ.
Mol Cell Biol. 2008 Nov;28(22):6828-43. doi: 10.1128/MCB.01297-08. Epub 2008 Sep 15.
PMID 18794358
Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1.
Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, Huntly BJ, Gottgens B, Bycroft M.
Nat Struct Mol Biol. 2010 May;17(5):617-9. doi: 10.1038/nsmb.1797. Epub 2010 Apr 18.
PMID 20400950
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


This paper should be referenced as such :
JL Huret
t(9;22)(p13;q13) PAX5/BRD1
Atlas Genet Cytogenet Oncol Haematol. 2014;18(11):862-864.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Translocations implicated (Data extracted from papers in the Atlas)

 t(9;22)(p13;q13) PAX5/BRD1

External links

PAX5 (9p13.2) BRD1 (22q13.33)

PAX5 (9p13.2) BRD1 (22q13.33)

Mitelman databaset(9;22)(p13;q13)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databasePAX5::BRD1 [MCList]  PAX5 (9p13.2) BRD1 (22q13.33)
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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indexed on : Fri Oct 8 16:37:05 CEST 2021

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