Disease relevance of PAX5

• Deregulated expression of PAX5 in medulloblastoma [1].
• Hereby, we analyzed routine biopsies from 360 acute leukemias of lymphoid (ALLs) and myeloid (AMLs) origin with a specific anti-PAX5 monoclonal antibody [2].
• PAX5 expression in acute leukemias: higher B-lineage specificity than CD79a and selective association with t(8;21)-acute myelogenous leukemia [2].
• The t(9;14) translocation associated with the B cell tumor lymphoplasmacytoid lymphoma juxtaposes the PAX5 gene into the vicinity of the IGH locus to deregulate PAX5 expression [3].
• Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray [4].

High impact information on PAX5

• Pax5 restricts the developmental options of lymphoid progenitors to the B cell lineage by repressing the transcription of lineage-inappropriate genes and simultaneously activating the expression of B-lymphoid signaling molecules [5].
• Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter [6].
• Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes [7].
• In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments [7].
• The B cell-specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2 [8].

Chemical compound and disease context of PAX5

• In the desmoplastic variant of medulloblastoma, PAX5 expression was restricted to the reticulin-producing proliferating tumor areas containing undifferentiated cells; PAX5 was not expressed in the reticulin-free nonproliferating islands undergoing neuronal differentiation [1].

Biological context of PAX5

• These data suggest that deregulated expression of PAX5 correlates positively with cell proliferation and inversely with neuronal differentiation in desmoplastic medulloblastoma [1].
• Real-time reverse transcription-PCR studies in t(8;21)-AML showed a similar up-regulation of PAX5 transcript in all of the 8 tested samples (including 4 cases that were negative at anti-PAX5 immunostaining), suggesting that PAX5 is expressed in t(8;21)-AML more widely than shown by immunohistochemistry [2].
• Aberrant promoter methylation of the transcription factor genes PAX5 alpha and beta in human cancers [9].
• Two of the CpG islands identified mapped to the 5' untranslated region of the PAX5 alpha and beta genes [9].
• Expression in cell lines with dense methylation of either the PAX5 alpha or beta promoter region was restored after treatment with the demethylating agent 5-Aza-2'-deoxycytidine [9].

Anatomical context of PAX5

• Blasts from 150 B-cell ALLs showed strong PAX5 nuclear expression, paralleling that of CD79a in the cytoplasm [2].
• Conversely, PAX5 was not detected in 50 T-cell ALLs, including 20 cases aberrantly coexpressing CD79a [2].
• Silencing of PAX5 gene by upregulation of B-lymphocyte-induced maturation protein-1 (PRDM1) is essential for terminal differentiation of B cells to plasma cells [4].
• Using paraffin-embedded bone marrow biopsy sections, we found PAX5/BSAP was expressed in 72% (18/25) of cases overall with an intensity ranging from weak (10, 56%) to strong (8, 44%) [4].
• PAX5-gene expression is restricted to the mesencephalon-rhombencephalon boundary and the spinal cord [10].

Associations of PAX5 with chemical compounds

• Cultivation of Pax5(-/-) pro-B cells on OP9 cells expressing the Notch ligand Delta-Like1 (OP9-DL1) in the presence of IL-7 efficiently induced T and NK cell potential [11].
• Thus, BSAP/Pax5A was constitutively expressed in the multipotent EML cell line, which can be directed toward the myeloid lineage by culture with interleukin-3 (IL-3) and retinoic acid [12].
• To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer [13].
• Together with fracture and densitometry data from the original study, relationships were examined between BMD and serum IGF-I, IGFBP-3, testosterone, estradiol, BSAP, and urine NTx, both at baseline and during treatment with alendronate, to gain possible insights into the pathogenesis of male osteoporosis [14].
• Whereas BSAP did not change significantly, S-NTX decreased significantly by risedronate treatment [15].

Physical interactions of PAX5

• We hypothesize that premature Blimp-1 expression coupled to altered and deficient Pax5 expression causes some proliferating B cells to prematurely differentiate to plasma cells in MM [16].
• The NLS sequence in the central domain of BSAP binds to the C-terminal 98-amino acid fragment of importin alpha1 [17].

Regulatory relationships of PAX5

• Interestingly, PAX5(+) t(8;21)-AML also expressed CD79a and/or CD19 (major transcriptional targets of PAX5 in B-cells) in 10 of 12 evaluable cases [2].
• Transient Notch signaling induces NK cell potential in Pax5-deficient pro-B cells [11].

Other interactions of PAX5

• Distinct promoters mediate the regulation of ebf1 gene expression by interleukin-7 and pax5 [18].
• The PAX5 beta gene encodes for the transcription factor B cell-specific activating protein that, in turn, directly regulates CD19, a gene shown to negatively control cell growth [9].
• CEBPA, PAX5 and PU1 were negative for all cell lines tested except in the three positive BCP-cell lines [19].
• We report in the present paper a preliminary in situ hybridization study of PAX3-, PAX5- and PAX6-gene expression during human embryonic development [10].
• We show here that ID2, which can inactivate E2A and perhaps PAX5, is not detectable in normal B cells but is strongly and uniformly expressed in HRS cells of all cases of classical HL [20].

Analytical, diagnostic and therapeutic context of PAX5

• PAX5 transcripts were readily detectable in clinical materials with a wide variety of B-cell neoplasms by reverse transcriptase-mediated polymerase chain reaction (PCR) [21].
• Electrophoretic mobility shift assays demonstrate that the isoforms possess specific DNA binding activity and recognize the PAX-5 consensus binding sites [22].
• Although the N-terminal paired (DNA-binding) domain of BSAP also conferred nuclear localization when coupled to green fluorescent protein, this domain did not bind to importin alpha1 in the yeast two-hybrid assay [17].
• Molecular cloning of t(9;14)(p13;q32) revealed juxtaposition of the PAX5 to the immunoglobulin heavy chain gene (IGH), although breakpoints on both genes were variable [23].
• RESULTS: PAX5 expression was found in 50 patients with bladder TCC but in no patient from the control group [24].

References