Mutant NPM1 Maintains the Leukemic State through HOX Expression
Menée in vitro et in vivo sur des modèles de leucémie myéloïde aiguë présentant un gène NMP1 muté, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de gènes HOX, la protéine NPMC1 localisée dans le cytoplasme favorise la survie des cellules leucémiques
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.
Cancer Cell 2018