Impaired proteolysis of noncanonical RAS proteins drives clonal hematopoietic transformation Journal Article


Authors: Chen, S.; Vedula, R. S.; Cuevas-Navarro, A.; Lu, B.; Hogg, S. J.; Wang, E.; Benbarche, S.; Knorr, K.; Kim, W. J.; Stanley, R. F.; Cho, H.; Erickson, C.; Singer, M.; Cui, D.; Tittley, S.; Durham, B. H.; Pavletich, T. S.; Fiala, E.; Walsh, M. F.; Inoue, D.; Monette, S.; Taylor, J.; Rosen, N.; McCormick, F.; Lindsley, R. C.; Castel, P.; Abdel-Wahab, O.
Article Title: Impaired proteolysis of noncanonical RAS proteins drives clonal hematopoietic transformation
Abstract: 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. SIGNIFICANCE: 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. © 2022 The Authors; Published by the American Association for Cancer Research.
Keywords: leukemia; genetics; metabolism; protein kinase inhibitor; protein degradation; transcription factor; transcription factors; protein kinase inhibitors; ras protein; ras proteins; guanosine triphosphate; protein p21; proto-oncogene proteins p21(ras); cullin; cullin proteins; proteolysis; humans; human; lztr1 protein, human
Journal Title: Cancer Discovery
Volume: 12
Issue: 10
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2022-10-01
Start Page: 2434
End Page: 2453
Language: English
DOI: 10.1158/2159-8290.Cd-21-1631
PUBMED: 35904492
PROVIDER: scopus
PMCID: PMC9533010
DOI/URL:
Notes: Article -- Export Date: 1 November 2022 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    425 Rosen
  2. Sebastien Monette
    150 Monette
  3. Benjamin Heath Durham
    117 Durham
  4. Hana Cho
    21 Cho
  5. Michael Francis Walsh
    156 Walsh
  6. Katherine Knorr
    9 Knorr
  7. Elise Marguerite Fiala
    15 Fiala
  8. Simon John Hogg
    26 Hogg
  9. Sisi Chen
    14 Chen
  10. Eric Wang
    12 Wang
  11. Daniel Cui
    6 Cui
  12. Michael Emet Zuri Singer
    8 Singer
  13. Bin Lu
    6 Lu
  14. Robert Stanley
    14 Stanley
  15. Won Jun Kim
    11 Kim