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.
Highlights
Acute myeloid leukemia (AML) is a disease in which the differentiation of hematopoietic progenitor cells is blocked resulting in unregulated expansion of leukemic blasts that is rapidly fatal if untreated
A requirement for DDX5 in proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells was described (Lin et al, 2012). In these cells DDX5 interacts with MAML1 to promote the expression of NOTCH-regulated genes, this study showed that DDX5 is required for initiation of T-ALL in vivo but it remains unclear whether DDX5 inhibition slows progression of established T-ALL or any other cancer
We investigated whether the ability of AML cell lines to proliferate was dependent on DDX5 by measuring the effect of DDX5 depletion on cell proliferation over time after retroviral-mediated shRNA transduction into the cells
Summary
Acute myeloid leukemia (AML) is a disease in which the differentiation of hematopoietic progenitor cells is blocked resulting in unregulated expansion of leukemic blasts that is rapidly fatal if untreated. DDX5 knockdown in breast cancer cells with Ddx gene amplification blocked their proliferation and resulted in downregulated expression of DNA replication factors. DDX5 knockdown in breast cancer cells lacking Ddx gene amplification did not affect the expression of DNA replication factors and these cells continued to proliferate. A requirement for DDX5 in proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells was described (Lin et al, 2012) In these cells DDX5 interacts with MAML1 to promote the expression of NOTCH-regulated genes, this study showed that DDX5 is required for initiation of T-ALL in vivo but it remains unclear whether DDX5 inhibition slows progression of established T-ALL or any other cancer
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