Chronic myeloid leukemia (CML) results from transformation of a primitive hematopoietic cell by the BCR-ABL gene. The BCR-ABL tyrosine kinase (TK) inhibitor imatinib is highly effective in inducing remissions and improving survival in CML patients but does not eradicate primitive malignant hematopoietic stem and progenitor cells (HSPC), which persist in CML patients in remission on imatinib. Therefore patients need continued treatment to maintain remission and may be at risk for relapse. In the preceding grant period we have extensively investigated mechanisms of response and resistance of CML progenitors to imatinib. Our results indicate that imatinib and BCR-ABL TK inhibitors, including dasatinib and nilotinib, effectively inhibit BCR-ABL TK activity in CML progenitors and markedly inhibit progenitor proliferation, but induce only modest increase in apoptosis. Quiescent CML progenitors are particularly resistant to apoptosis following imatinib treatment. Persistence of CML HSPC despite effective BCR-ABL TK inhibition indicates the need for additional strategies to enhance elimination of malignant stem cells. We have shown that CML progenitors-treated with imatinib and other BCR-ABL TK inhibitors continue to be responsive to microenvironmental growth signals that help maintain their viability.
In Specific Aim 1 will further investigate the role of microenvironmental interactions in resistance of CML hematopoietic stem cells to apoptosis following imatinib treatment using in vitro stromal co-coculture and in vivo mouse models of CML. We will investigate whether the a4b1 integrins and N-cadherin adhesion receptors contribute to protection of CML HSPC by the microenvironment. We will also investigate the role of Wnt-?-catenin signaling in CML stem cell maintenance following imatinib treatment. We have found that treatment with the histone deacetylase (HDAC) inhibitor LAQ824 in combination with imatinib results in significantly increased apoptosis of CML CD34+ cells, which is associated with markedly reduced expression of the anti-apoptotic protein Mcl-1.
In Specific Aim 2 we will further investigate whether HDAC inhibitors can selectively and effectively induce apoptosis and eliminate CML HSPC in combination with imatinib, and will investigate mechanisms of apoptotic targeting of CML HSPC. We will investigate the mechanisms of Mcl-1 inhibition and the role of Mcl-1 downregulation in mediating HDAC effects on CML HSPC. We will also identify and investigate additional HDAC-inhibitor induced alterations in gene regulation that may lead to enhanced apoptotic targeting of CML HSPC using chromatin immunoprecipitation and gene expression array based approaches. Successful completion of these studies is expected to lead to future clinical application of these approaches to eliminate leukemia stem cells and potentially achieve cure in CML patients.

Public Health Relevance

The BCR-ABL kinase inhibitor imatinib is highly effective in inducing remissions and improving survival in chronic myeloid leukemia (CML) patients but does not eradicate primitive leukemia stem and progenitor cells. Therefore patients need continued treatment to maintain remission and may be at risk for relapse and additional methods to enhance elimination of CML stem cells are required. The studies proposed here will investigate mechanisms of protection of leukemia stem cells from elimination by imatinib and examine whether blocking these mechanisms will enhance their elimination. The results if these studies will have direct application to clinical approaches to eliminate leukemia stem cells and potentially achieve cure in CML patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-HEME-D (02))
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Merritt, William D
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City of Hope/Beckman Research Institute
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Ladds, Marcus J G W; Pastor-Fernández, Andrés; Popova, Gergana et al. (2018) Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib. PLoS One 13:e0195956
Pellicano, Francesca; Park, Laura; Hopcroft, Lisa E M et al. (2018) hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival. Blood 131:1532-1544
Ladds, Marcus J G W; van Leeuwen, Ingeborg M M; Drummond, Catherine J et al. (2018) A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nat Commun 9:1107
Bhatia, Ravi (2017) Novel approaches to therapy in CML. Hematology Am Soc Hematol Educ Program 2017:115-120
Mukherjee, Kaushiki; Sha, Xiaojin; Magimaidas, Andrew et al. (2017) Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia. Oncotarget 8:10809-10821
Mesa, Ruben A; Jamieson, Catriona; Bhatia, Ravi et al. (2017) NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018. J Natl Compr Canc Netw 15:1193-1207
Negi, Vijay; Vishwakarma, Bandana A; Chu, Su et al. (2017) Hoxa9 and Hoxa10 induce CML myeloid blast crisis development through activation of Myb expression. Oncotarget 8:98853-98864
Irvine, David A; Zhang, Bin; Kinstrie, Ross et al. (2016) Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep 6:25476
Carter, Bing Z; Mak, Po Yee; Mu, Hong et al. (2016) Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med 8:355ra117
Li, Ling; Bhatia, Ravi (2015) Role of SIRT1 in the growth and regulation of normal hematopoietic and leukemia stem cells. Curr Opin Hematol 22:324-9

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