Acquired dependence of acute myeloid leukemia on the DEAD-box RNA helicase DDX5.

Abstract

Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS). This apoptotic response can be blocked either by BCL2 overexpression or treatment with the ROS scavenger N-acetyl-L-cysteine. Combining DDX5 knockdown with a BCL2 family inhibitor cooperates to induce cell death in AML cells. By inhibiting DDX5 expression in vivo, we show that DDX5 is dispensable for normal hematopoiesis and tissue homeostasis. These results validate DDX5 as a potential target for blocking AML.

• Authors: Anthony Mazurek, Youngkyu Park, Cornelius Miething, John E Wilkinson, Jesse Gillis, Scott W Lowe, Christopher R Vakoc, Bruce Stillman
• Journal: Cell reports (Cell Rep) Vol. 7 Issue 6 Pg. 1887-99 (Jun 26 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 24910429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Reactive Oxygen Species
• Ddx5 protein, human
• DEAD-box RNA Helicases

Topics

• Aged
• Animals
• Apoptosis (physiology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• DEAD-box RNA Helicases (antagonists & inhibitors, metabolism)
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Mice
• Mice, Transgenic
• Reactive Oxygen Species (metabolism)