Key Points Simultaneous inhibition of Cdk9 and PI3K in human AML cells liberates Bak from both Mcl-1 and Bcl-xL, inducing Bak-dependent apoptosis. Dual inhibitors of Cdk9 and PI3K, such as PIK-75, have broad activity against malignant cells including human AML cells.

Loss of p53-dependent apoptosis contributes to the development of hematologic malignancies and failure to respond to treatment. Proapoptotic Bcl-2 family member Puma is essential for apoptosis in HoxB8-immortalized interleukin-3 (IL-3)-dependent myeloid cell lines (FDM cells) provoked by IL-3 deprivation. p53 and FoxO3a can transcriptionally regulate Puma. To investigate which transcriptional regulator is responsible for IL-3 deprivation-induced Puma expression and apoptosis, we generated wild-type (WT), p53 ؊/؊ , and FoxO3a ؊/؊ FDM cells and found that p53 ؊/؊ but not FoxO3a ؊/؊ cells were protected against IL-3 withdrawal. Loss of p21 cip/waf , which is critical for p53-mediated cell-cycle arrest, afforded no protection against IL-3 deprivation. A survival advantage was also observed in untransformed p53 ؊/؊ hemato poietic progenitor cells cultured in the presence or absence of cytokines. In response to IL-3 deprivation, increased Puma protein levels in p53 ؊/؊ cells were substantially delayed compared with WT cells. Increased p53 transcriptional activity was detected after cytokine deprivation. This was substantially less than that induced by DNA damage and associated not with increased p53 protein levels but with loss of the p53 regulator, MDM2. Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2. Activated p53 transcriptionally upregulates Puma, which initiates apoptosis. (Blood. 2010;115:344-352) IntroductionThe maintenance of hematopoietic stem and progenitor cells depends on lineage-specific growth factors, such as interleukin-3 (IL-3). In the absence of cytokine signals, hematopoietic cells exit the cell cycle and commit to apoptosis by pathways regulated by the Bcl-2 family of apoptosis regulators. Evading this commitment permits cells to survive and proliferate in the absence of cytokines and constitutes an important step to tumor formation. 1 Understanding the pathways by which cytokine signaling regulates proliferation and suppresses apoptosis in hematopoietic cells provides insight to the abnormal regulation of these responses in hematologic malignancies.Acute myeloid leukemia (AML) with 17p deletions or mutations lose p53 function. This is associated with poorer outcomes and response to treatment, in part, as a result of loss of p53-dependent apoptosis. 2,3 In chronic lymphocytic leukemia (CLL) or AML, loss of p53 may also promote clonogenic proliferation and generation of malignant cells with a stem cell-like phenotype. 4 The p53 tumor suppressor functions to regulate the cell cycle and apoptosis in response to a range of cellular stresses such as double-stranded DNA breaks, exposure to genotoxic drugs commonly used to treat malignancies, and abnormal regulation of the cell cycle. 5 Other evidence indicates p53 also regulates apoptosis in response to cytokine and substrate deprivation. 6,7 p53 also functions to limit the capacity of somatic cells to produce induced pluripotential stem cells through unknown mechanisms. [8][9][10][11] The mechanism of p53-dependen...

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