Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation

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  • Sisi Chen
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Rahul S. Vedula
    2Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Antonio Cuevas-Navarro
    3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
  • Bin Lu
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Simon J. Hogg
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Eric Wang
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Salima Benbarche
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Katherine Knorr
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Won Jun Kim
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Robert F. Stanley
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hana Cho
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Caroline Erickson
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Michael Singer
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Dan Cui
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Steven Tittley
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Benjamin H. Durham
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Tatiana S. Pavletich
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Elise Fiala
    4Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Michael F. Walsh
    4Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Daichi Inoue
    5Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.
  • Sebastien Monette
    6Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, The Rockefeller University, New York, New York.
  • Justin Taylor
    7Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, Florida.
  • Neal Rosen
    8Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Frank McCormick
    3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
  • R. Coleman Lindsley
    2Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Pau Castel
    3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
  • Omar Abdel-Wahab
    1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

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<jats:title>Abstract</jats:title> <jats:sec> <jats:title/> <jats:p>Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 2221</jats:p> </jats:sec>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 12 (10), 2434-2453, 2022-07-29

    American Association for Cancer Research (AACR)

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