Journal
CANCER CELL
Volume 34, Issue 3, Pages 499-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.08.005
Keywords
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Categories
Funding
- Cancer Prevention Research Institute of Texas [RP140001, RP160283]
- Baylor Research Advocates for Student Scientists
- Baylor College of Medicine Medical Scientist Training Program
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [18568]
- European Research Council (ERC) [740230, 725725]
- Leukemia and Lymphoma Society [CPRIT RP160693]
- MDACC MDS-AML Moonshot program [CA016672]
- American Cancer Society [PF-17-010-01-CDD]
- Claudia Adams Barr Program in Innovative Basic Cancer Research
- Damon Runyon Cancer Research Foundation [DRG-2196-14]
- [DK092883]
- [CA183252]
- [CA222736]
- [DK113705]
- [CA125123]
- [CA215452]
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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 down-regulation 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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