ArticleCancer discovery2022
Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Integrating 730,947 exome sequences with clinical literature improves gene discovery.medRxiv : the preprint server for health sciences · 2026Article
- LZTR1 Loss Reduces Vimentin Expression and Motility in Hep3B Hepatocellular Carcinoma Cells.International journal of molecular sciences · 2026Article
- Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer.iScience · 2026Review
- Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.Nature communications · 2025Article
- Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.Cell reports · 2025Article
- Ubiquitin-independent pathway regulates the RIT1-MAPK pathway in chordoma progression.Cell death & disease · 2025Article
- Structural basis for LZTR1 recognition of RAS GTPases for degradation.Science (New York, N.Y.) · 2025Article
- RIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma.Cancer research · 2025Article
- Review
- RIT1 Promotes the Proliferation of Gliomas Through the Regulation of the PI3K/AKT/c-Myc Signalling Pathway.Journal of cellular and molecular medicine · 2025Article
- Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice.JCI insight · 2024Article
- Molecular impact of mutations in RNA splicing factors in cancer.Molecular cell · 2024Review
- Article
- Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.Nature genetics · 2024Article
- Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome.Blood advances · 2023Article
- RIT1 regulates mitosis and promotes proliferation by interacting with SMC3 and PDS5 in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2023Article
- Mutated ZRSR2 and CUL3 accelerate clonal evolution and confer venetoclax resistance via RAS signaling pathway in blastic plasmacytoid dendritic cell neoplasm.International journal of hematology · 2023Article
- LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion.Cell death & disease · 2023Article
- RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.Science advances · 2023Article
- Biological insights in non-small cell lung cancer.Cancer biology & medicine · 2023Review
Corrections and comments
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Authors and funding
27 authors at 5 institutions in 2 countries.
Funding
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. This article is highlighted in the In This Issue feature, p. 2221.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.