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BCL6 represents a therapeutic target in E2A-PBX1 and MLL-rearranged acute lymphoblastic leukemia

ABSTRACT: We used ChIPseq to identify target genes of BCL6 that are involved in leukemogenesis of E2A-PBX1 and MLL-AF4 pre-B ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59541 | GEO | 2019/12/31

REPOSITORIES: GEO

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Self-enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Project description:We used ChIPseq in primary pre-B acute lymphomablastic leukemia (ALL) cells to identify target genes of the oncogenes TCF3-PBX1 and BCL6 that are involved in leukemogenesis of TCF3-PBX1 pre-B ALL. ChIP-seq using E2A (TCF3), PBX1, p300 and BCL6 antibodies in ICN12 cells (primary pre-B acute lymphomablastic leukemia)

2015-02-08 | E-GEOD-59538 | biostudies-arrayexpress

Microarray data of mouse primary E2A-PBX1 leukemia and preleukemia cells

Project description:Microarray data of mouse primary E2A-PBX1 leukemias and preleukemia cells were compared to wild-type B-cell progenitor cells Aberrant activation of signaling pathways has been linked to leukemogenesis, however, little is known about cell signaling perturbations induced by fusion transcription factors. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the chimeric fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) ALL. We describe here signaling network remodeling by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. E2A-PBX1 binds and activates the transcription of its target genes ZAP70, SYK and LCK, which encode kinases upstream of PLCγ2. Efficient shRNA-mediated depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise compound knockdown of ZAP70, SYK or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy. Inhibition of SYK, LCK and SFK with small molecule inhibitors, including dasatinib, was highly effective in reducing pPLCγ2 and inhibiting proliferation of preBCR+ leukemias in vitro and in vivo. Combination small molecule inhibition of SYK, LCK and SFK showed promising preclinical efficacy for preBCR+/E2A-PBX1+ leukemias. These studies demonstrate that E2A-PBX1 induces signaling pathway perturbations upstream of PLCγ2, which render leukemias amenable to targeted therapeutic inhibition.

2016-05-03 | GSE81010 | GEO

Chromatin Immunoprecipitation of E2A-PBX1 in the cell line 697

Project description:Data from "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels The experiment showed direct targets of the fusion protein. In the manuscript, individual gene targets are explained, along with DNA motifs that the fusion protein bound to. Demonstrates the "direct" targets of the E2A-PBX1 leukemia fusion protein, which is a feature of about 5% of all chilldhood leukemia. Comparison of the ChIP pull-down from E2A antibody in an E2A-PBX1 positive cell line, compared to the input DNA. There are 3 replicate experiments

2013-11-23 | E-GEOD-52653 | biostudies-arrayexpress

Identification of negative feedback regulators in response to acute activation of BCR-ABL1 kinase signaling in MLL-AF4 and E2A-PBX1 acute lymphoblastic leukemia

Project description:Human B cell lineage acute lymphoblastic leukemia (ALL) cells carrying MLL-AF4 (SEM; BEL) and E2A-PBX1 (697) gene rearrangements were transduced with the mouse ecotropic receptor to permit subsequent entry of retroviral BCR-ABL1 GFP and GFP empty vectors (EV) pseudotyped with murine ecotropic envelope. GFP expression was measured by flow cytometry. Transductions with BCR-ABL1 GFP and GFP empty vectors (EV) were performed in the presence and absence of 2 mmol/l Imatinib (TKI). Washout of Imatinib in one series of experiments is indicated with an arrow. To study gene expression changes in MLL-AF4 and E2A-PBX1 B cell lineage ALL cells that were transduced with empty vectors (EV), BCR-ABL1 GFP in the presence of Imatinib (BCR-ABL1 OFF), washout of Imatinib (BCR-ABL1 ON) and subsequent re-addition of Imatinib, microarray analyses were performed.

2015-12-29 | GSE40836 | GEO

Chromatin Immunoprecipitation of E2A-PBX1 in the cell line 697

2013-11-23 | GSE52653 | GEO

Global gene expression profile of CNS-infiltrating E2A-PBX1+/preBCR+ ALL cells

Project description:In order to elucidate mechanism of resistance to BTKi and dasatinib in CNS-infiltrating leukemia cells and to investigate the CNS homing of E2A-PBX1/preBCR+ ALL cells, we performed global transcriptome analysis by RNA sequencing. RNA was isolated from CNS-infiltrating cells from vehicle, dasatinib, ibrutinib, dasatinib + ibrutinib-treated mice

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Chronic active pre-B cell receptor signaling drives BCL6 expression and represents a therapeutic target in a distinct subtype of acute lymphoblastic leukemia

Project description:BCL6fl/fl mouse bone marrow pre-B cells were transduced with an TCF3-PBX1 vector. The TCF3-PBX1 transduced BCL6fl/fl pre-B cells were then transduced with an empty vector (EV), or a Cre vector for Cre-mediated BCL6 deletion. Effect of BCL6 deletion in the TCF3-PBX1 pre-B cells were studied by Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. TCF3-PBX1 transduced BCL6fl/fl mice bone marrow pre-B cells were tranduced with an empty vector (EV) or a Cre vector for BCL6 deletion

2015-02-08 | E-GEOD-59332 | biostudies-arrayexpress

SNP arrays to detect copy number changes in t(1;19) E2A-PBX1 positive leukemias

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2013-11-23 | GSE52654 | GEO

SNP arrays to detect copy number changes in t(1;19) E2A-PBX1 positive leukemias

2013-11-23 | E-GEOD-52654 | biostudies-arrayexpress

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