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
em 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mielomonocítica Crônica
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Proteínas Proto-Oncogênicas
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Proteínas Monoméricas de Ligação ao GTP
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Proteínas de Ligação a DNA
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GTP Fosfo-Hidrolases
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Proteínas de Membrana
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Mutação
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2018
Tipo de documento:
Article