Journal
CANCER CELL
Volume 33, Issue 1, Pages 44-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.11.012
Keywords
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Categories
Funding
- LLS [SCOR 7004-14, SCOR 7006-13]
- NCI [R01CA173636, R35197594, R01CA198089, K08CA169055]
- Leukemia Lymphoma Society (LLS) [SCOR 9328-16]
- Chemotherapy Foundation
- American Society of Hematology under the ASH-AMFDP partnership [ASHAMFDP-20121]
- Robert Wood Johnson Foundation
- Translational Research Oncology Training Program from Iris & Junming Le Foundation
- Swiss National Science Foundation [PBBEP-144806, PZ00P3-161145]
- Swiss Cancer League/Swiss Cancer Research [KFS-3005-08-2012, KFS-3858-02-2016]
- Foundation for the Fight against Cancer, Switzerland
- Foundation Peter Anton and Anna Katharina Miescher for research in hematology
- Swiss Society of Hematology
- Nora van Meeuwen-Hafliger Foundation
- SWISS BRIDGE Foundation
- LLS
- NIH [K08CA181507]
- Sumitomo Life Welfare
- Culture Foundation Foreign Medical Research Grant
- Lady Tata Memorial Trust International Awards
- Clinical Scholars Biomedical Research Training Program Fellowship from the Charles A. Dana Foundation
- NIH/NCI Cancer Center Support Grant [P30CA008747, P30CA008748]
- NATIONAL CANCER INSTITUTE [K08CA181507, R25CA020449, K08CA169055, P30CA008748, R01CA198089, R01CA173636, R35CA197594] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [U54OD020355] Funding Source: NIH RePORTER
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Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras(G12D) 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.
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