Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
Cancer Cell
; 33(1): 44-59.e8, 2018 01 08.
Article
en En
| MEDLINE
| ID: mdl-29275866
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia Mielomonocítica Crónica
/
Proteínas Proto-Oncogénicas
/
Proteínas de Unión al GTP Monoméricas
/
Proteínas de Unión al ADN
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GTP Fosfohidrolasas
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Proteínas de la Membrana
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Mutación
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2018
Tipo del documento:
Article