Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Nutt, Stephen L.; Urbánek, Pavel; Rolink, A G; Busslinger, Meinrad

doi:10.1101/gad.11.4.476

Cited by 379 publications

(396 citation statements)

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“…Previous loss-of-function analyses identified an essential role for Pax5 in controlling V H -DJ H recombination of distal but not proximal V H genes in pro-B cells (Nutt et al 1997;Hesslein et al 2003). Here we have reported the unexpected finding that ectopic expression of Pax5 promotes efficient rearrangement of proximal rather than distal V H genes in pro-T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Restoration of Pax5 expression in Pax5 −/− pro-B cells suppresses this multilineage potential and rescues development to mature B cells, thus identifying Pax5 as the critical B-lineage commitment factor that restricts the developmental options of lymphoid progenitors to the B-cell pathway ). In addition, Pax5 controls the second, B-cell-restricted step of V H -DJ H recombination, as rearrangements of the distal (5Ј) V H J558 genes are ∼50-fold reduced in Pax5 −/− pro-B cells, although D H -J H recombination occurs at normal frequency (Nutt et al 1997). Despite this defect, the distal V H genes are present in accessible chromatin, as indicated by their germ-line transcription and histone H3 acetylation in Pax5 −/− pro-B cells (Hesslein et al 2003).…”

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confidence: 99%

“…Both transcription factors appear to control the initial D H -J H rearrangement step by activating the expression of RAG1 and RAG2 (Bain et al 1994;Lin and Grosschedl 1995;O'Riordan and Grosschedl 1999) and by promoting the accessibility of the D H -J H region to the V(D)J recombinase (Romanow et al 2000). In the absence of Pax5, B-lymphopoiesis proceeds in the bone marrow to early pro-B cells (fraction B; Urbánek et al 1994;Nutt et al 1997), which still retain a broad lympho-myeloid developmental potential characteristic of uncommitted progenitors Rolink et al 1999). Restoration of Pax5 expression in Pax5 −/− pro-B cells suppresses this multilineage potential and rescues development to mature B cells, thus identifying Pax5 as the critical B-lineage commitment factor that restricts the developmental options of lymphoid progenitors to the B-cell pathway ).…”

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Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

Fuxa¹,

Skok²,

Souabni³

et al. 2004

Genes Dev.

378

457

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Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

Fuxa¹,

Skok²,

Souabni³

et al. 2004

Genes Dev.

378

457

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“…33 Furthermore, Pax5 homozygous deletion in mice showed that Pax5 is crucial for the transition from D H J H to V H D H J H IGH rearrangement, and especially for distal rearrangement. 34 Although we were unable to detect a significant frequency difference regarding IGH Figure 3 Disease-free survival (DFS) and cumulative incidence of relapse according to PAX5 (paired-box domain 5) status (a) DFS. At 3 years, estimated DFS was 57% (95%; CI 44-69%), 64% (95%; CI 38-84%) and 43% (95%; CI 20-64%), in the normal, deleted and structural mutant PAX5 group, respectively (P ¼ 0.33, by the log-rank test).…”

Section: Discussionmentioning

confidence: 88%

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

et al. 2009

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Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count. Leukemia (2009Leukemia ( ) 23, 1989Leukemia ( -1998 doi:10.1038/leu.2009; published online 9 July 2009 Keywords: BCP-ALL; oncogenesis; BCR-ABL1; PAX5; TCF3-PBX1 Introduction PAX5 (paired-box domain 5) is the guardian of the B-cell identity as stated in a recent review. 1 This transcription factor belongs to the family of paired-box domain transcription factors. 2 Its expression is initiated during early stages of B-cell differentiation beginning at the pro-B stage, 3 and is turned off to allow terminal B-cell differentiation. 4 The Pax5 homozygous deletion in murine models leads to the trans-or de-differentiation of B-cells into several other hematopoietic cell lineages. [5][6][7] PAX5 is thus involved both in the maintenance of B-cell identity and in the control of terminal B-cell differentiation.Deregulations and mutations of key differentiation factors are frequently found in lymphomas and leukemias. Translocations associated with hematologic malignancies involving PAX5 exemplify PAX5 dual function. On one hand, the t(9;14)(p13;q32) translocation brings the potent enhancer of the IGH gene close to the PAX5 promoter leading to an aberrant expression of a normal PAX5 protein. 8,9 This translocation is recurrent in small plasmacytoid B-cell lymphocytic lymphomas and diffuse large B-cell lymphomas. 10 It emphasizes the importance of PAX5 downregulation during terminal B-cell differentiation. 9 On the other hand, PAX5 translocations have also been associated with a block of early B-cell differentiation because the PAX5-ETV6 chimeric protein, product of the dic(9;12)(p13;p13), is associated with B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). 11 Additional PAX5 fusion partner genes have been identified as HIPK1 (chromosomal band 1p13), 12-14 LOC392027 (7p12.1), 15 AUTS2 (7q11.1), 13 POM121 (7q11), 14 ELN (7q11), 16 JAK2 (9p24), 14 SLCO1B3 (12p12), 15 DACH1 (13q21), 14 PML (15q24), 17 ZNF5...

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“…DJ H -distal V H gene segments are blocked from undergoing V H -to-DJ H rearrangement in pro-B cells from Pax5-deficient mice (Urbanek et al, 1994;Nutt et al, 1997;Hesslein et al, 2003). Until recently, there was evidence for two roles of Pax5 in controlling V H -to-DJ H rearrangements: (a) facilitating rearrangement of distal V H genes by inducing IgH locus contraction (Fuxa et al, 2004), and (b) removing histone H3 methylated at lysine 9, a marker of repressed chromatin, from the V H locus, making V H genes accessible for V H -to DJ H recombination (Johnson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

Espinoza

Feeney

2007

Molecular Immunology

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The molecular mechanisms that control the temporal and lineage-specific accessibility, as well as the rearrangement frequency of V H genes for V H -to-DJ H recombination, are not fully understood. We previously found a positive correlation between the extent of histone acetylation and the differential rearrangement frequency of individual V H genes. Here, we demonstrated that poorly rearranging V H genes are more highly associated with histone H3 dimethylated at lysine 9, a marker of repressive chromatin, than frequently rearranging V H genes. We also observed a positive relationship between the differential binding of Pax5 to individual V H S107 genes and rearrangement frequency. Furthermore, we showed that accessibility of the regions flanking the Pax5 binding site and the RSS to restriction enzyme cleavage correspond with the differential rearrangement frequency of the V H S107 family members. In addition, we found that the CpG sites located in the coding regions of V H genes are methylated in general, while the extent of DNA methylation drops dramatically near the RSS. For the V H S107 family, one CpG site located 101 bp upstream of the RSS showed variable methylation that correlates with rearrangement frequency, and the methylation status of a CpG site located 34 bp downstream of the RSS could also favor the rearrangement of V1 over V11. These findings suggest that the extent of histone modifications, chromatin accessibility, DNA methylation, as well as the differential binding of Pax5 to V H coding regions, could all influence the rearrangement frequency of individual V H genes, although some of these mechanisms are not strictly B cell specific.

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Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Cited by 379 publications

References 100 publications

Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

Pax5 inducesV-to-DJrearrangements and locus contraction of theimmunoglobulin heavy-chaingene

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

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