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 #
5P01CA049639-24
Application #
8722324
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
24
Fiscal Year
2014
Total Cost
$285,055
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Eiring, A M; Page, B D G; Kraft, I L et al. (2015) Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia 29:586-97
Zhang, Weiguo; Gao, Chen; Konopleva, Marina et al. (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20:2363-74
Tao, Wenjing; Leng, Xiaohong; Chakraborty, Sandip N et al. (2014) c-Abl activates janus kinase 2 in normal hematopoietic cells. J Biol Chem 289:21463-72
Thall, Peter F; Nguyen, Hoang Q; Zohar, Sarah et al. (2014) Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome. J Am Stat Assoc 109:931-943
Mak, P Y; Mak, D H; Mu, H et al. (2014) Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML. Apoptosis 19:698-707
Jin, Ick Hoon; Liu, Suyu; Thall, Peter F et al. (2014) Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical Trials with Delayed Outcomes. J Am Stat Assoc 109:525-536
Benjamini, Ohad; Kantarjian, Hagop; Rios, Mary Beth et al. (2014) Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma 55:2879-86
Havelange, Violaine; Ranganathan, Parvathi; Geyer, Susan et al. (2014) Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 123:2412-5
Ohanian, Maro; Kantarjian, Hagop M; Quintas-Cardama, Alfonso et al. (2014) Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 14:155-162.e1
Zabriskie, Matthew S; Eide, Christopher A; Tantravahi, Srinivas K et al. (2014) BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 26:428-42

Showing the most recent 10 out of 220 publications