Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE45260 | GEO | 2013/08/01
SECONDARY ACCESSION(S): PRJNA193336
REPOSITORIES: GEO
Similar Datasets
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 40 samples comprising sevenfold replicates of transductions with empty vector, wild type PAX5 and 4 mutant PAX5 constructs
2013-08-01 | E-GEOD-45260 | biostudies-arrayexpress
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia.
2014-04-06 | GSE45834 | GEO
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 10 samples of J558 murine myeloma cells infected with MSCV-Puro-IRES-GFP (PIG) empty vector (EV; three independent replicates), MSCV-PIG Pax5 WT (WT; three independent replicates), and MSCV-PIG Pax5 G183S (Mut; four independent replicates). Cells were selected with puromycin after infection for 5-7 days, subsequently cells were sorted for GFP and IgM expression by FACS.
2014-04-06 | E-GEOD-45834 | biostudies-arrayexpress
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13 . Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional analysis of the PAX5 germline variants demonstrated reduced transcriptional activity, as well as decreased interaction with Groucho-4. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia.
| EGAS00001000447 | EGA
Project description:PAX5, one of nine members of the mammalian paired box (PAX) family of transcription factors, plays an important role in B cell development. Approximately one-third of individuals with pre-B acute lymphoblastic leukemia (ALL) acquire heterozygous inactivating mutations of PAX5 in malignant cells, and heterozygous germline loss-offunction PAX5 mutations cause autosomal dominant predisposition to ALL. At least in mice, Pax5 is required for pre-B cell maturation, and leukemic remission occurs when Pax5 expression is restored in a Pax5-deficient mouse model of ALL. Together, these observations indicate that PAX5 deficiency reversibly drives leukemogenesis. PAX5 and its two most closely related paralogs, PAX2 and PAX8, which are not mutated in ALL, exhibit overlapping expression and function redundantly during embryonic development. However, PAX5 alone is expressed in lymphocytes, while PAX2 and PAX8 are predominantly specific to kidney and thyroid, respectively. We show that forced expression of PAX2 or PAX8 complements PAX5 loss-of-function mutation in ALL cells as determined by modulation of PAX5 target genes, restoration of immunophenotypic and morphological differentiation, and, ultimately, reduction of replicative potential. Activation of PAX5 paralogs, PAX2 or PAX8, ordinarily silenced in lymphocytes, may therefore represent a novel approach for treating PAX5-deficient ALL. In pursuit of this strategy, we took advantage of the fact that, in kidney, PAX2 is upregulated by extracellular hyperosmolarity. We found that hyperosmolarity, at potentially clinically achievable levels, transcriptionally activates endogenous PAX2 in ALL cells via a mechanism dependent on NFAT5, a transcription factor coordinating response to hyperosmolarity. We also found that hyperosmolarity upregulates residual wild type PAX5 expression in ALL cells and modulates gene expression, including in PAX5-mutant primary ALL cells. These findings specifically demonstrate that osmosensing pathways may represent a new therapeutic target for ALL and more broadly point toward the possibility of using gene paralogs to rescue mutations driving cancer and other diseases.
2018-09-11 | GSE109860 | GEO
Project description:PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here we studied the function of PAX5-ETV6 and PAX5- FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested Blymphopoiesis at the pro-B-to-pre-B cell transition and, contrary to their proposed dominantnegative role, did not interfere with the expression of most Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressor in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-BCR signaling and migration/adhesion, which could contribute to the proliferation, survival and tissue infiltration of leukemic B-cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein. 36 samples in total: A) 24 RNA-Seq samples in 5 cell types: pro-B (5 genotypes, 2-4 replicates) large pre-B (2 genotypes, 2 replicates each) small pre-B (1 genotype, 2 replicates) lymph node (1 genotype, 3 replicates) bone marrow (1 genotype, 2 replicates) B) 12 ChIP-Seq samples in 2 cell types: pro-B (H3K27me3, H3K9ac, H3K4me2, H3K4me3, H3K27ac, 1 replicate each; Pax5Etv6 ChIP, Prd ChIP, 2 replicates each; Pax5 ChIP 1 replicate) lymph node (1 genotype, 2 replicates).
2016-07-30 | E-GEOD-84987 | biostudies-arrayexpress
Project description:PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here we studied the function of PAX5-ETV6 and PAX5- FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested Blymphopoiesis at the pro-B-to-pre-B cell transition and, contrary to their proposed dominantnegative role, did not interfere with the expression of most Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressor in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-BCR signaling and migration/adhesion, which could contribute to the proliferation, survival and tissue infiltration of leukemic B-cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein.
2017-02-06 | GSE84987 | GEO
Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL. Gene expression profiling was performed on cells isolated from lymph nodes of Stat5b-CA x Ebf1+/- and Stat5b-CA x Rag2-/- leukemic mice and pre B cells sorted from bone marrow of C57BL/6 mice and Stat5b-CA transgenic mice. 17 Samples.
2011-05-09 | E-GEOD-25645 | biostudies-arrayexpress
Project description:To investigate the molecular basis for the B cell developmental arrest in Pax5R31Q/– mice, we performed RNA-sequencing (RNA-seq) with ex vivo sorted Pax5+/+ and Pax5R31Q/– pro-B cells. We identified Pax5-activated and Pax5-repressed genes that were no longer properly regulated by the Pax5-R31Q protein in Pax5R31Q/– pro-B cells. Notably, these genes were only a subset of the activated and repressed genes identified by comparing Pax5+/+ and Pax5–/– pro-B cells, which raised the question whether binding of the Pax5-R31Q protein may be selectively lost at the subset of deregulated genes in Pax5R31Q/– pro-B cells. By using a Pax5 paired domain antibody for chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) of short-term cultured Pax5+/+ and Pax5R31Q/– pro-B cells, we identified all associated Pax5 binding sites. Common Pax5 peaks had a similar Pax5-binding density in contrast to the strong binding difference observed at the unique peaks present in Pax5+/+ pro-B cells. To investigate a correlation between the loss of Pax5 binding and gene expression, we focused our analysis on Pax5 peaks in the TSS region of activated genes. We systematically investigated the correlation between loss of Pax5 binding at the TSS and down-regulation of gene expression in Pax5R31Q/– pro-B cells. The ratio of Pax5 binding between Pax5R31Q/– and Pax5+/+ pro-B cells at the TSS of these activated genes was significantly reduced compared to that of expressed non-regulated genes. We next explored whether the Pax5-binding difference at the TSS also correlated with the magnitude of gene expression difference. The loss of Pax5 binding at the TSS also correlated with the degree of expression change in Pax5R31Q/– pro-B cells compared to Pax5+/+ pro-B cells. We conclude therefore that the selective DNA-binding of Pax5-R31Q is responsible for the observed gene expression differences in Pax5R31Q/– pro-B cells.
2022-07-06 | GSE182463 | GEO
Project description:PAX5, a transcription factor essential for B-cell development, has been found as a frequent target of abnormalities in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) cases, showing point mutations, deletions, as well as translocations with several partner genes. We identified four novel PAX5 fusion partner genes by performing a screening on BCP-ALL cases with 9p rearrangements. Copy Number Variation analysis of translocated samples showed that few significant cooperative genetic lesions are present in addition to the translocation event, suggesting that it might have a primary role in leukemogenesis.
2015-03-02 | E-MTAB-2416 | biostudies-arrayexpress