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Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE196378 | GEO | 2022/04/16

REPOSITORIES: GEO

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Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

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

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

2022-04-16 | GSE196375 | GEO

Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

Project description:Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. 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.

| S-EPMC9160250 | biostudies-literature

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis

| PRJNA804538 | ENA

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (RNA-Seq)

| PRJNA804541 | ENA

Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

Project description:Nuclear Vav3 is required for canonical PRC1 activity in B-cell lymphoblastic leukemogenesis (CUT&RUN)

| PRJNA804543 | ENA

A central role for canonical PRC1 in shaping the 3D nuclear landscape.

Project description:Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system.

| S-EPMC7328521 | biostudies-literature

Maintenance of Leukemic Cell Identity by the Activity of the Polycomb Complex PRC1

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-10-21 | E-GEOD-67552 | biostudies-arrayexpress

Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-16 | GSE249218 | GEO

Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival.

Project description:Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressing acute lymphoblastic leukemia.

| S-EPMC3412345 | biostudies-literature

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