1. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.
- Author
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Carr RM, Vorobyev D, Lasho T, Marks DL, Tolosa EJ, Vedder A, Almada LL, Yurcheko A, Padioleau I, Alver B, Coltro G, Binder M, Safgren SL, Horn I, You X, Solary E, Balasis ME, Berger K, Hiebert J, Witzig T, Buradkar A, Graf T, Valent P, Mangaonkar AA, Robertson KD, Howard MT, Kaufmann SH, Pin C, Fernandez-Zapico ME, Geissler K, Droin N, Padron E, Zhang J, Nikolaev S, and Patnaik MM
- Subjects
- Animals, Cell Cycle Proteins metabolism, GTP Phosphohydrolases metabolism, Gene Expression Profiling methods, Gene Expression Regulation, Leukemic, Histone-Lysine N-Methyltransferase metabolism, Kaplan-Meier Estimate, Leukemia, Myelomonocytic, Chronic metabolism, Leukemia, Myelomonocytic, Chronic therapy, Membrane Proteins metabolism, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Signal Transduction genetics, Stem Cell Transplantation methods, Transplantation, Homologous, Exome Sequencing methods, Xenograft Model Antitumor Assays methods, Polo-Like Kinase 1, Mice, Cell Cycle Proteins genetics, GTP Phosphohydrolases genetics, Histone-Lysine N-Methyltransferase genetics, Leukemia, Myelomonocytic, Chronic genetics, Membrane Proteins genetics, Mutation, Myeloid-Lymphoid Leukemia Protein genetics, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins genetics
- Abstract
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS
G12D , define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.- Published
- 2021
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