Many patients with chronic myeloid leukemia (CML) attain excellent responses on imatinib (Gleevec). However, recurrence is the rule upon drug discontinuation, consistent with survival of fully leukemogenic CML progenitor cells in the presence of drug. Therefore, therapy must continue lifelong, often despite significant side effects. It is not well understood why CML progenitor cells survive in patients on imatinib, and therefore It is difficult to develop specific approaches to eradicate residual leukemia. The long-term objective of this project is to improve the prognosis and quality of life of CML patients, by understanding the mechanisms underlying the survival of CML progenitor cells during therapy. We have preliminary data suggesfing that CML progenitor cells can use alternative signals to compensate forthe loss of BCR-ABL acfivity upon treatment with BCR-ABL kinase inhibitors. Further we have evidence that inhibition ofthe stem cell factor recptor KIT Is a critical mediator of imatinib effcts on CML cells. Lastly, we have identified a gene expression signature associated with primary cytogenetic resistance to imatinib and have evidence that betacatenin may be involved in the regulation ofthe signature genes. We propose three Specific Aims:
AIM 1. To elucidate mechanisms of CML progenitor cell survival upon inhibition of BCR-ABL .We will assess whether CML progenitor cells are dependent on BCR-ABL or whether JAK2-dependent stroma cellderived factors can protect them from the effects of BCR-ABL inhibitors.
AIM 2. To determine the role of KIT for CML progenitor cell survival upon inhibition of BCR-ABL. We will test whether inhibifion of KIT is essential for the biological effects of imatinib on CML progenitor cells and whether KIT is required for BCR-ABL to induce CML.
AIM 3. To determine the role of p-catenin for imatinib resistance. We will determine whether betacatenin is a master regulator of genes associated with primary imatinib failure, whether beta-catenin acfivafion confers imatinib resistance, and how beta-catenin is regulated in CML progenitor cells.

Public Health Relevance

Imatinib, the effecfive therapeutic standard for CML, fails to eradicate the disease and thus must be given life-long, at a cost of more than $20,000/patient/year, and often despite side effects. Additionally, 15-20% of pafients exhibit primary resistance to imatinib and have a high risk of disease progression. The overarching aim of this application is to identify mechanisms that allow CML progenitor cells to survive despite imafinib inhibition of BCR-ABL. Results from this work provide a rafional basis to develop curafive therapies capable of eliminafing all CML cells, so that imafinib therapy can be discontinued.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA049639-20A2
Application #
8000080
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
20
Fiscal Year
2010
Total Cost
$299,139
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Gambacorti-Passerini, Carlo; Cortes, Jorge E; Lipton, Jeff H et al. (2018) Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103:1298-1307
Boddu, Prajwal; Shah, Abdul Rashid; Borthakur, Gautam et al. (2018) Life after ponatinib failure: outcomes of chronic and accelerated phase CML patients who discontinued ponatinib in the salvage setting. Leuk Lymphoma 59:1312-1322
Kornblau, Steven M; Ruvolo, Peter P; Wang, Rui-Yu et al. (2018) Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival. Haematologica 103:810-821
Zhang, Weiguo; Ly, Charlie; Ishizawa, Jo et al. (2018) Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica 103:1642-1653
Alhuraiji, Ahmad; Kantarjian, Hagop; Boddu, Prajwal et al. (2018) Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol 93:84-90
Ishizawa, Jo; Nakamaru, Kenji; Seki, Takahiko et al. (2018) Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. Cancer Res 78:2721-2731
Boddu, Prajwal; Benton, Christopher B; Wang, Wei et al. (2018) Erythroleukemia-historical perspectives and recent advances in diagnosis and management. Blood Rev 32:96-105
Ruvolo, Peter P; Ruvolo, Vivian R; Burks, Jared K et al. (2018) Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res 1865:959-969
Cortes, Jorge E; Gambacorti-Passerini, Carlo; Deininger, Michael W et al. (2018) Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol 36:231-237
Sasaki, Koji; Kantarjian, Hagop; O'Brien, Susan et al. (2018) Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase. Cancer 124:1160-1168

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