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

Author

Listed:
  • R. C. Nayak

    (University of Cincinnati College of Medicine
    University of Cincinnati College of Medicine)

  • K. H. Chang

    (University of Cincinnati College of Medicine
    The University of Texas MD Anderson Cancer Center)

  • A. K. Singh

    (University of Cincinnati College of Medicine
    University of Cincinnati College of Medicine)

  • M. Kotliar

    (University of Cincinnati College of Medicine)

  • M. Desai

    (University of Cincinnati College of Medicine)

  • A. M. Wellendorf

    (University of Cincinnati College of Medicine)

  • M. Wunderlich

    (University of Cincinnati College of Medicine)

  • J. Bartram

    (University of Cincinnati College of Medicine)

  • B. Mizukawa

    (University of Cincinnati College of Medicine)

  • M. Cuadrado

    (Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca
    Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca)

  • P. Dexheimer

    (University of Cincinnati College of Medicine)

  • A. Barski

    (University of Cincinnati College of Medicine)

  • X. R. Bustelo

    (Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca
    Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca)

  • N. N. Nassar

    (University of Cincinnati College of Medicine)

  • J. A. Cancelas

    (University of Cincinnati College of Medicine
    University of Cincinnati College of Medicine)

Abstract

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.

Suggested Citation

  • R. C. Nayak & K. H. Chang & A. K. Singh & M. Kotliar & M. Desai & A. M. Wellendorf & M. Wunderlich & J. Bartram & B. Mizukawa & M. Cuadrado & P. Dexheimer & A. Barski & X. R. Bustelo & N. N. Nassar & , 2022. "Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30651-7
    DOI: 10.1038/s41467-022-30651-7
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    1. Charles G. Mullighan & Christopher B. Miller & Ina Radtke & Letha A. Phillips & James Dalton & Jing Ma & Deborah White & Timothy P. Hughes & Michelle M. Le Beau & Ching-Hon Pui & Mary V. Relling & She, 2008. "BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros," Nature, Nature, vol. 453(7191), pages 110-114, May.
    2. Charles G. Mullighan & Salil Goorha & Ina Radtke & Christopher B. Miller & Elaine Coustan-Smith & James D. Dalton & Kevin Girtman & Susan Mathew & Jing Ma & Stanley B. Pounds & Xiaoping Su & Ching-Hon, 2007. "Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia," Nature, Nature, vol. 446(7137), pages 758-764, April.
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