Oncotarget

Research Papers:

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 and Beverly S. Mitchell _

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Oncotarget. 2016; 7:74917-74930. https://doi.org/10.18632/oncotarget.12493

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Abstract

Min Huang1, Jacqueline S. Garcia2, Daniel Thomas2,3, Li Zhu4, Le Xuan Truong Nguyen1, Steven M. Chan2,3, Ravindra Majeti1,2,3, Bruno C. Medeiros1,2, Beverly S. Mitchell1,2

1Stanford Cancer Institute, Stanford University, Stanford, California, USA

2Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA

3Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA

4Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

Correspondence to:

Beverly S. Mitchell, email: bmitchell@stanford.edu

Keywords: autophagy, NPM1, HEXIM1, BET inhibitors, AML

Received: March 14, 2016     Accepted: September 26, 2016     Published: October 06, 2016

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.


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