Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells

Min Huang, Jacqueline S. Garcia, Daniel Thomas, Li Zhu, Le Xuan Truong Nguyen, Steven M. Chan, Ravindra Majeti, Bruno C. Medeiros, Beverly S. Mitchell

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

Original languageEnglish
Pages (from-to)74917-74930
Number of pages14
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished or Issued - 2016
Externally publishedYes

Keywords

  • AML
  • Autophagy
  • BET inhibitors
  • HEXIM1
  • NPM1

ASJC Scopus subject areas

  • Oncology

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