Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)
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ABSTRACT:
PROVIDER: PRJNA804541 | ENA |
REPOSITORIES: ENA
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Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis
| PRJNA804538 | ENA
Project description:Acute B-cell lymphoblastic leukemia (B-ALL) represents a multiclonal evolution of B-cell progenitors endowed with both tumor-initiating and propagating properties. We have previously shown that the concurrent overexpression and activation of both the Rac guanine nucleotide exchange factor (RacGEF) Vav3 and Rac GTPases is required for BCR-ABL-mediated leukemogenesis. Here, we show that upon BCR-ABL expression, Vav3 expression becomes predominantly nuclear. In this location, Vav2 interacts with BCR-ABL, Rac, and the canonical polycomb repression complex proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for B-cell proliferation and Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, H2A(K119) mono-ubiquitination (H2AK119Ub), and repression of downstream target loci. Vav3 deficiency results in de-repression and repression of loci encoding negative regulators of cell proliferation and oncogenic transcriptional factors, respectively. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.
2022-04-16 | GSE196375 | GEO
Project description:Acute B-cell lymphoblastic leukemia (B-ALL) represents a multiclonal evolution of B-cell progenitors endowed with both tumor-initiating and propagating properties. We have previously shown that the concurrent overexpression and activation of both the Rac guanine nucleotide exchange factor (RacGEF) Vav3 and Rac GTPases is required for BCR-ABL-mediated leukemogenesis. Here, we show that upon BCR-ABL expression, Vav3 expression becomes predominantly nuclear. In this location, Vav2 interacts with BCR-ABL, Rac, and the canonical polycomb repression complex proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for B-cell proliferation and Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, H2A(K119) mono-ubiquitination (H2AK119Ub), and repression of downstream target loci. Vav3 deficiency results in de-repression and repression of loci encoding negative regulators of cell proliferation and oncogenic transcriptional factors, respectively. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.
2022-04-16 | GSE196377 | GEO
Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)
| PRJNA804543 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-04-16 | GSE196378 | GEO
Project description:1. Loss of RING1B substantially disrupts nuclear architecture. 2. PRC1 mediated looping can occur at a Mb scale and is independent of CTCF. 3. Polycomb mediated looping is driven by canonical PRC1 complexes. 4. Trimeric PRC1-mediated interactions occur in vitro and in vivo. 5. Gene up-regulation does not directly lead to the loss of PRC1 loops.
2019-12-15 | GSE134826 | GEO
Project description:Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here we find that the non-canonical PRC1.1 complex, as identified by mass spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is co-targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3 suggesting a gene regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls distinct gene clusters involved in unique cell biological processes required for leukemic cell viability. K562 cells were transduced with lentiviral GFP-fusion vectors encoding GFP-CBX2, PCGF1-GPF, PCGF2-GFP, PCGF4-GFP, GFP-RING1A or GFP-RING1B. K562 cells expressing GFP-fusions at relatively low levels were sorted and expanded and subsequently crosslinked. ChIP reactions were performed using the following antibodies: anti-GFP (ab290, Abcam), anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), and anti-KDM2B (ab137547, Abcam). Furthermore, ChIP reactions were performed using primary AML CD34+ and Peripheral Blood (PB) CD34+ cells using anti-H3K27me3 (07-449, Millipore), anti-H3K4me3 (ab8580, Abcam), anti-H2AK119ub (D27C4, Cell Signaling Technology), anti-KDM2B (ab137547, Abcam).
2015-11-24 | E-GEOD-54580 | biostudies-arrayexpress
Project description:Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here we find that the non-canonical PRC1.1 complex, as identified by mass spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is co-targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3 suggesting a gene regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls distinct gene clusters involved in unique cell biological processes required for leukemic cell viability.
2015-11-24 | GSE54580 | GEO
Project description:Polycomb group proteins form two main complexes, PRC2 and PRC1, which generally coregulate their target genes. Here, we show that PRC1 components act as neoplastic tumor suppressors independently of PRC2 function. By mapping the distribution of PRC1 components and the histone H3K27me3 mark, we identify genes that acquire PRC1 and H3K27me3 in larvae, and a much larger set of genes bound by PRC1 in the absence of H3K27me3 in larval tissues. These genes massively outnumber canonical targets and they are preeminently involved in the regulation of cell proliferation, signaling and polarity. Mutation in PRC1 components specifically deregulates this set of genes, whereas canonical targets are derepressed in both PRC1 and PRC2 mutants. In human ES cells, PRC1 components colocalize with H3K27me3 like in Drosophila embryos, whereas they are selectively recruited to a large set of proliferation and signaling-associated genes in differentiated cell types, showing that the redeployment of PRC1 components during development is evolutionarily conserved. Comparative study of Polycomb group proteins and histon marks during development with ChIP-Seq and RNA-Seq data in eye discs and wing discs (L3 stage) in Drosophila
2016-07-18 | E-GEOD-74080 | biostudies-arrayexpress