Chronic myelogenous leukemia (CML) is propagated by small populations of leukemia stem cells (LSC). BCR- ABL tyrosine kinase inhibitors (TKI) including Imatinib, Nilotinib and Dasatinib are very effective in the treatment of CML. However, TKI do not eliminate CML LSC and leukemia usually recurs when treatment is stopped. The majority of CML patients require indefinite TKI treatment to maintain remission, with associated risk of non-compliance, recurrence, long-term toxicity, and substantial financial burden. Furthermore some CML patients are refractory or resistant to TKI treatment and have a very poor prognosis. Although TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, and inhibits their proliferation, only modest induction of apoptosis is seen, suggesting that kinase-independent mechanisms contribute to LSC persistence. We have a longstanding research interest in studying LSC regulatory mechanisms, identifying key mechanisms of resistance of LSC to TKI treatment, and developing novel strategies for eliminating LSC and improve outcomes for CML patients. We have recently found that the NAD-dependent SIRT1 deacetylase is overexpressed in CML LSC. SIRT1 inhibition using RNAi or pharmacologic inhibitors significantly reduces growth and survival of CML compared to normal stem cells, with further inhibition of CML LSC growth seen in combination with TKI. SIRT1 inhibition can even target CML LSC from patients resistant to TKI treatment. SIRT1 inhibition results in increased p53 acetylation and transcriptional activity in CML LSC, and the effects of SIRT1 inhibition on CML LSC can be prevented by p53 knockdown or expression of an acetylation-deficient p53 construct. These results indicate that SIRT1 effects on CML LSC are mediated by p53 acetylation and activation. The p53 gene plays a critical role in the cellular response to genotoxic and oncogenic stress, by inducing cell cycle arrest or apoptosis. SIRT1 inhibition is an attractive approach to activate p53 signaling in CP CML LSC, where p53 mutations are rare, and in BC CML LSC that do not harbor p53 mutations. In addition, activation of p53 by direct targeting of HDM2, a well characterized regulator of p53 expression, could also be useful for targeting CML LSC. The proposed studies will use conditional genetic murine models to evaluate the role of SIRT1 activation in modulating p53 activity in BCR-ABL expressing LTHSC;determine the roles of SIRT1 and p53 in leukemia initiation versus maintenance of established leukemia;and definitively determine the role of p53 activation in mediating effects of SIRT1 inhibition in CML LSC (Specific Aim 1). In addition, we will use clinically relevant primary leukemia models to conduct preclinical studies to test the ability of newly developed SIRT1 inhibitors and HDM2 inhibitors to effectively and selectively target CML LSC, to determine whether SIRT1 and HDM2 inhibitors cause different patterns of p53 target gene activation;and whether combining these inhibitors can enhance elimination of CML LSC. (Specific Aim 2). The results of these studies will also be applicable to other leukemias and solid tumors that have SIRT1 overexpression.
Although BCR-ABL tyrosine kinase inhibitors (TKI) are very effective in the treatment of chronic myelogenous leukemia (CML), a subset of patients is resistant to TKI treatment, and even in TKI responsive patients leukemia stem cells (LSC) usually persist and cause disease recurrence when treatment is stopped. We have shown that the NAD-dependent SIRT1 deacetylase plays an important role in maintaining CML LSC and protecting them from TKI treatment, by modulating p53 activity. We will validate the role of SIRT1 and p53 in regulating CML LSC growth, and as potential molecular therapeutic targets in CML, using genetic mouse models;and conduct preclinical studies of SIRT1 and HDM2 inhibitors to target and eliminate CML LSC.
|Wang, Zhiqiang; Liu, Zheng; Wu, Xiwei et al. (2014) ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance. PLoS Genet 10:e1004414|
|Gallipoli, Paolo; Cook, Amy; Rhodes, Susan et al. (2014) JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood 124:1492-501|
|Li, Ling; Osdal, Tereza; Ho, Yinwei et al. (2014) SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 15:431-46|
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|Chen, WenYong; Bhatia, Ravi (2013) Roles of SIRT1 in leukemogenesis. Curr Opin Hematol 20:308-13|
|Zhang, Bin; Li, Min; McDonald, Tinisha et al. (2013) Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-*-catenin signaling. Blood 121:1824-38|
|Gallipoli, Paolo; Pellicano, Francesca; Morrison, Heather et al. (2013) Autocrine TNF-* production supports CML stem and progenitor cell survival and enhances their proliferation. Blood 122:3335-9|
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|Hamilton, Ashley; Helgason, G Vignir; Schemionek, Mirle et al. (2012) Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 119:1501-10|
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