title: 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.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mazurek
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Youngkyu
authors.initials: Y
authors.lastname: Park
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 415 E. 68(th) Street, Box 373, New York, NY 10065, USA.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Miething
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gillis
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 415 E. 68(th) Street, Box 373, New York, NY 10065, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. Electronic address: stillman@cshl.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Stillman
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases