Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus

Abstract

IntroductionB-cell commitment critically depends on the transcription factor Pax5 (BSAP), which is required for B-cell development beyond an early pro-B-cell stage in the bone marrow. 1 Pax5 Ϫ/Ϫ pro-B cells are uncommitted lymphoid progenitors with a broad developmental potential and are able to differentiate into mature B cells only once their multilineage potential is suppressed by restoration of Pax5 expression. 2 Conversely, the loss of Pax5 expression by conditional gene inactivation converts committed pro-B cells with a restricted B-cell potential into lymphoid progenitors with a broad developmental potential. 3 Moreover, ectopic Pax5 expression in hematopoietic stem cells (HSCs) and their progeny strongly skews the developmental options of lymphoid progenitors by promoting B-cell development at the expense of T lymphopoiesis. 4 Consistent with its B-lineage commitment function, Pax5 is exclusively expressed within the hematopoietic system from the pro-B to the mature B-cell stage and is essential for maintaining the identity and function of B lymphocytes. 5 At the molecular level, Pax5 fulfills a dual role in gene regulation. It activates a multitude of B-cellspecific genes, some of which code for essential components of (pre)BCR signaling. 6 At the same time, Pax5 represses lineageinappropriate genes with important functions in receptor signaling, cell adhesion, migration, and transcriptional regulation in other hematopoietic lineages. 2,7 Hence, Pax5 controls the B-cell phenotype by shutting down inappropriate signaling systems and by simultaneously facilitating B-lymphoid signal transduction from the (pre)BCR.Tumors of hematopoietic origin are frequently associated with specific chromosomal translocations, which result in the activation of proto-oncogenes controlling differentiation, proliferation, or cell survival. In B-cell non-Hodgkin lymphomas (B-NHLs), these proto-oncogenes are often deregulated by translocation adjacent to regulatory elements of the immunoglobulin heavy-chain (IgH) locus on human chromosome 14q32. 8 The PAX5 gene on chromosome 9p13 is involved in the recurrent translocation t(9;14)(p13;q32), which juxtaposes the intact coding sequences of PAX5 in opposite orientation next to the constant gene region of the IgH locus. [9][10][11] The molecular analysis of 5 breakpoints revealed that the t(9;14) translocation arises in germinal center B cells as a result of misguided IgH class switch recombination or somatic hypermutation. In 3 cases, the breakpoints were found in the switch S or S␣ region of the IgH locus and in exon 1B of PAX5, which resulted in replacement of the 2 alternative PAX5 promoters by antisense promoters present in the IgH switch region. [10][11][12] The breakpoints of 2 additional translocations occurred 1.8 kb (KIS-1 lymphoma) or 2 kb upstream of the distal exon 1A of PAX5, which brought the 2 PAX5 promoters under the control of the juxtaposed intronic E enhancer or 3Ј locus control region of the IgH locus. 9,10,13 The regulatory t(9;14)(p13;q32) translocation may pa...

Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray

“…In contrast, translocation of the PAX5 gene to the enhancer region of the Ig heavy chain gene [t(9;14)(p13.2;q32)] or point mutations of the 5Ј regulatory region of the PAX5 gene leads to its overexpression, which is associated with B cell lineage lymphomas (27)(28)(29). Also, experimental overexpression of wild-type PAX5 can transform lymphocytes (30,31). Therefore, an aberrant PAX5 may behave in a dominant-negative fashion at the pre-B stage of B cell development, resulting in ALL; its forced expression in a more mature B cell can lead to lymphoma.…”

Human BSAP and BLIMP1 conform an autoregulatory feedback loop

“…15,16 Moreover, recent studies demonstrate the oncogenic role of BSAP by mutations or alterations in the expression of PAX5 gene. [17][18][19][20][21] Murine B-lymphocyte-induced maturation protein-1 (BLIMP1), or its human homologue positive regulatory domain I binding factor 1 (PRDI-BF1), is a transcription factor that has been demonstrated to act as a master regulator required 10 and sufficient 22 for the generation and for the prolonged maintenance of PCs. 23 To differentiate into PCs, BLIMP1 reduces B-cell proliferation as a consequence of MYC repression, 24 and decreases B-cell functions as a result of PAX5 repression.…”

Rare expression of BSAP (PAX-5) in mature T-cell lymphomas

“…30 Contrary to the assumption that BSAP, as a gene expressed exclusively in B-and not T-lymphocytes, might have no role in T-cell lymphomagenesis, experimental evidence showed that aberrant BSAP expression in thymocytes drives malignant transformation and, surprisingly, that the T-cell lineage, at least in vitro, is particularly prone to the oncogenic potential of BSAP. 27 Our single case suggests that BSAP might also play a role in in vivo T-cell lymphomagenesis not only in immature, but also in mature T-cell lymphomas. Interestingly, in non-lymphoid hematological neoplasms, BSAP is expressed in t(8;21) acute myelogenous leukemia, where similar to its function in developing B-cells, it upregulates its major transcriptional targets, CD79a and CD19.…”

“…25 Importantly in that context, in experimental mice models, knockin experiments with ectopic BSAP expression, under the control of the IgH locus in thymocytes, can also lead to the development of (immature) T-lymphoblastic lymphomas. 27 In addition to its functional importance for B-cell development and identity maintenance, BSAP appears to be involved in B-cell lymphomagenesis in a particular subset of aggressive diffuse large B-cell lymphomas 28 and probably in some lymphoplasmacytic lymphomas carrying the t(9;14), 29 although the latter is controversial in the literature. 30 Contrary to the assumption that BSAP, as a gene expressed exclusively in B-and not T-lymphocytes, might have no role in T-cell lymphomagenesis, experimental evidence showed that aberrant BSAP expression in thymocytes drives malignant transformation and, surprisingly, that the T-cell lineage, at least in vitro, is particularly prone to the oncogenic potential of BSAP.…”