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

doi:10.1016/j.ccell.2018.08.005

Mutant NPM1 Maintains the Leukemic State through HOX Expression

Cancer Cell. 2018 Sep 10;34(3):499-512.e9. doi: 10.1016/j.ccell.2018.08.005.

Authors

Lorenzo Brunetti¹, Michael C Gundry², Daniele Sorcini³, Anna G Guzman⁴, Yung-Hsin Huang⁵, Raghav Ramabadran⁶, Ilaria Gionfriddo³, Federica Mezzasoma³, Francesca Milano³, Behnam Nabet⁷, Dennis L Buckley⁸, Steven M Kornblau⁹, Charles Y Lin¹⁰, Paolo Sportoletti³, Maria Paola Martelli³, Brunangelo Falini³, Margaret A Goodell¹¹

Affiliations

¹ Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, 06132 Perugia, Italy.
² Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, 06132 Perugia, Italy.
⁴ Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Leukemia and Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: goodell@bcm.edu.

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.

Keywords: AML; CRISPR; HOX; MEIS1; NPM1; XPO1; acute myeloid leukemia; dTAG; nuclear export; selinexor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Animals
Cell Differentiation / genetics
Cell Line, Tumor
Cell Nucleus / metabolism
Cytoplasm / metabolism
Down-Regulation
Exportin 1 Protein
Female
Gene Expression Regulation, Leukemic*
Homeodomain Proteins / metabolism*
Humans
Hydrazines / pharmacology
Karyopherins / antagonists & inhibitors
Karyopherins / metabolism
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / mortality
Leukemia, Myeloid, Acute / pathology
Mice
Mutation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Nucleophosmin
Proteolysis
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear / metabolism
Triazoles / pharmacology
Xenograft Model Antitumor Assays

Substances

Homeodomain Proteins
Hydrazines
Karyopherins
NPM1 protein, human
Npm1 protein, mouse
Nuclear Proteins
Receptors, Cytoplasmic and Nuclear
Triazoles
Nucleophosmin
selinexor

Abstract

Publication types

MeSH terms

Substances

Grants and funding