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Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates

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  • Xiaorong Gu
  • Quteba Ebrahem
  • Reda Z Mahfouz
  • Metis Hasipek
  • Francis Enane
  • Tomas Radivoyevitch
  • Nicolas Rapin
  • Bartlomiej Przychodzen
  • Zhenbo Hu
  • Ramesh Balusu
  • Claudiu V Cotta
  • David Wald
  • Christian Argueta
  • Yosef Landesman
  • Maria Paola Martelli
  • Brunangelo Falini
  • Hetty Carraway
  • Bo T Porse
  • Jaroslaw P Maciejewski
  • Babal K Jha
  • Yogen Saunthararajah
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Nucleophosmin (NPM1) is amongst the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant-NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein-interactome by mass-spectrometry, and discovered abundant amounts of the master transcription factor driver of monocyte lineage-differentiation PU.1 (SPI1). Mutant-NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulo-monocytic lineage-fates, remained nuclear, but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating greater than 500 granulocyte and monocyte terminal-differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant-NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these non-cytotoxic treatments extended survival by greater than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant-NPM1 represses monocyte and granulocyte terminal-differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically-directed dosing of clinical small molecules.

Original languageEnglish
JournalThe Journal of clinical investigation
Volume128
Issue number10
Pages (from-to)4260-4279
ISSN0021-9738
DOIs
Publication statusPublished - 1 Oct 2018

ID: 54954225