Mutant NPM1 Maintains the Leukemic State through HOX Expression

Lorenzo Brunetti, Michael C. Gundry, Daniele Sorcini, Anna G. Guzman, Yung Hsin Huang, Raghav Ramabadran, Ilaria Gionfriddo, Federica Mezzasoma, Francesca Milano, Behnam Nabet, Dennis L. Buckley, Steven M. Kornblau, Charles Y. Lin, Paolo Sportoletti, Maria Paola Martelli, Brunangelo Falini, Margaret A. Goodell

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


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. Brunetti et al. show that specific loss of NPM1c from the cytoplasm leads to downregulation of HOX genes and differentiation in NPM1 mutant AML. Blocking NPM1c nuclear export by XPO1 inhibition reduces cytoplasmic NPM1c, promotes AML differentiation, and prolongs the survival of a mouse model of NPM1c+ AML.

Original languageEnglish
Pages (from-to)499-512.e9
JournalCancer Cell
Issue number3
StatePublished - 10 Sep 2018
Externally publishedYes


  • AML
  • HOX
  • MEIS1
  • NPM1
  • XPO1
  • acute myeloid leukemia
  • dTAG
  • nuclear export
  • selinexor


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