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Genome-wide maps of chromatin state in Ba/F3 cell with PAX5-KIDINS220 fusion protein

ABSTRACT: PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, using in vitro murine assays and ChIP-sequencing, we demonstrate that PAX5-K220 is a nuclear protein that inhibits PAX5 transcriptional activity in a dominant-negative fashion, resulting in a B-cell differentiation block. Gene expression analysis and ChIP-sequencing revealed that PAX5-K220 is associated with multiple pathways related to chemotaxis and migration.

ORGANISM(S): Mus musculus

PROVIDER: GSE129021 | GEO | 2019/03/30

REPOSITORIES: GEO

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PAX5-KIDINS220 gene expression array in Ba/F3 cells

Project description:PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed.We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. In addition, PAX5-K220 activates JAK2-STAT5 pathway through the repression of Socs5, a known negative regulator of JAK-STAT pathway. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. Luciferase reporter assay reveals that PAX5-K220 inhibits wild type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity.

2019-03-01 | GSE127485 | GEO

Genome-wide maps of chromatin state in Ba/F3 cell with PAX5-KIDINS220 fusion protein

Project description:Genome-wide maps of chromatin state in Ba/F3 cell with PAX5-KIDINS220 fusion protein

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PAX5-KIDINS220 gene expression array in Ba/F3 cells

Project description:PAX5-KIDINS220 gene expression array in Ba/F3 cells

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SPAG9-JAK2 gene expression array in Ba/F3 cells

Project description:SPAG9-JAK2 is a novel fusion gene identified in a pediatric patient with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). In this study, we performed functional analysis of the SPAG9-JAK2 fusion to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9-JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9-JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly up-regulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9-JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9-JAK2, but not SPAG9-JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9-JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9-JAK2 fusion.

2021-05-18 | GSE174578 | GEO

Novel PAX5 fusion genes in childhood B-Cell Precursors Acute Lymphoblastic Leukemia

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

Molecular role of the PAX5-ETV6 oncoprotein in promoting B cell acute lymphoblastic leukemia

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

Transcription profiling of mice Pax5 targets in B-macrophage bipotential lymphoma cells

Project description:B-macrophage bipotential lymphoma cells without Pax5 expression were reconstituted with the Pax5-estrogen receptor fusion protein and changes in transcription profiles in response to 4-hydroxytamoxifen were monitored in vivo

2007-09-01 | E-MEXP-1156 | biostudies-arrayexpress

PAX5 promotes heterocharomatin formation

Project description:Heterochromatin has a high density of DNA and low rates of gene transcription.H3k9me3 is a conserved histone modification, and is best known for its role in constitutive heterochromatin formation.H1155, which is a neuroendocrine large cell lung cancer cell line, has a dense nucleus and a high level of occupancy of H3K9me3. PAX5 is a neurogenesis and B lymphocyte development transcription factor, and endogenous expressed in neuroendocrine carcinoma, including H1155 cell line. To assess whether PAX5 promotes heterochromatin formation in H1155, we knock out PAX5 in H1155 cell (KO-PAX5) by CRISPR/Cas9 and use H3K9me3 to performed ChIP-seq.

2024-01-17 | GSE165035 | GEO

PAX5 transduction of Pax5-/- pro-B cells

Project description:PAX5 transduction of Pax5-/- pro-B cells

| PRJNA414096 | ENA

Inhibition of Inflammatory Signaling in Pax5 Mutant Cells Mitigates B-cell leukemogenesis against leukemia

Project description:We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions. PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers can be detected in neonatal blood spot samples of children who later developed B-cell precursor B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 loss results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. In vivo genetic downregulation of IL-6 in Pax5 mutant mice retards B-cell leukemogenesis. In vivo pharmacologic inhibition of IL-6 with a neutralizing IL-6 antibody in Pax5 mutant mice with B-ALL clears leukemic cells. This exciting novel IL 6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

2020-07-17 | GSE154589 | GEO

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