Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.

Kunimoto, 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; Shih, Alan H (2018). Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity. Cancer cell, 33(1), 44-59.e8. Cell Press 10.1016/j.ccell.2017.11.012

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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 NrasG12D 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

UniBE Contributor:

Meyer, Sara Christina

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1535-6108

Publisher:

Cell Press

Language:

English

Submitter:

Julia Elisa Garcia

Date Deposited:

27 Dec 2023 08:25

Last Modified:

27 Dec 2023 08:34

Publisher DOI:

10.1016/j.ccell.2017.11.012

PubMed ID:

29275866

Uncontrolled Keywords:

cancer epigenetics leukemia biology targeted therapeutics

BORIS DOI:

10.48350/190297

URI:

https://boris.unibe.ch/id/eprint/190297

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