Mutant NPM1 Maintains the Leukemic State through HOX Expression.
Cancer Cell
; 34(3): 499-512.e9, 2018 09 10.
Article
em En
| MEDLINE
| ID: mdl-30205049
ABSTRACT
NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
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MEDLINE
Assunto principal:
Proteínas Nucleares
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Leucemia Mieloide Aguda
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Regulação Leucêmica da Expressão Gênica
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Proteínas de Homeodomínio
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article