Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
05 10 2022
05 10 2022
Historique:
received:
15
12
2021
revised:
23
06
2022
accepted:
26
07
2022
pubmed:
30
7
2022
medline:
7
10
2022
entrez:
29
7
2022
Statut:
ppublish
Résumé
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. 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. This article is highlighted in the In This Issue feature, p. 2221.
Identifiants
pubmed: 35904492
pii: 707346
doi: 10.1158/2159-8290.CD-21-1631
pmc: PMC9533010
mid: NIHMS1828356
doi:
Substances chimiques
Cullin Proteins
0
LZTR1 protein, human
0
Protein Kinase Inhibitors
0
Transcription Factors
0
Guanosine Triphosphate
86-01-1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2434-2453Subventions
Organisme : NCI NIH HHS
ID : K08 CA204734
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009207
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197709
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA254838
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128239
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA265066
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157387
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251138
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242020
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA245122
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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