TitleCooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
Publication TypeJournal Article
Year of Publication2018
AuthorsKunimoto, Hiroyoshi, Meydan Cem, Nazir Abbas, Whitfield Justin, Shank Kaitlyn, Rapaport Franck, Maher Rebecca, Pronier Elodie, Meyer Sara C., Garrett-Bakelman Francine E., Tallman Martin, Melnick Ari, Levine Ross L., and Shih Alan H.
JournalCancer Cell
Date Published2018 Jan 08
KeywordsAnimals, Cell Transformation, Neoplastic, Dioxygenases, DNA-Binding Proteins, GTP Phosphohydrolases, Humans, Intracellular Signaling Peptides and Proteins, Leukemia, Myelomonocytic, Chronic, Membrane Proteins, Mice, Transgenic, Monomeric GTP-Binding Proteins, Mutation, Myeloproliferative Disorders, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Signal Transduction

<p>Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions.</p>

Alternate JournalCancer Cell
PubMed ID29275866
PubMed Central IDPMC5760367
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
U54 OD020355 / OD / NIH HHS / United States
R01 CA173636 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States
R25 CA020449 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35 CA197594 / CA / NCI NIH HHS / United States
K08 CA181507 / CA / NCI NIH HHS / United States