Chronic myeloid leukemia (CML) and about 20% of acute lymphoblastic leukemias (ALL) are characterized by expression of the oncogenic fusion protein Bcr-Abl that has constitutive tyrosine kinase activity. The selective Bcr-Abl antagonist imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor that has proven highly effective in the treatment of CML. Although effective, imatinib therapy is usually not curative. Imatinib fails to completely eliminate Bcr-Abl+ cells and the disease often relapses due to development of imatinib resistance. Also, Bcr-Abl+ ALL is refractory to treatment with imatinib. Targeting additional gene products may enhance the efficacy of imatinib in eliminating CML and Bcr-Abl+ ALL cells and lead to complete eradication of disease. We have designed an unbiased loss-of-function screen using RNA interference (RNAi) to identify such genes. We utilized a genome-wide lentiviral small hairpin RNA (shRNA) library in combination with microarray analysis to identify gene targets that, when inhibited, potentiate Bcr-Abl+ cell killing by imatinib. Our screen identified multiple genes that are components of a noncanonical Wnt/calcium signaling pathway whose biological role is poorly understood. We plan to further analyze these genes to determine if their inactivation effectively cooperates with imatinib in killing Bcr-Abl+ cells in vitro and in mouse models of CML and Bcr-Abl+ ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA133182-02
Application #
7869445
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$112,760
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Gregory, Mark A; D'Alessandro, Angelo; Alvarez-Calderon, Francesca et al. (2016) ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proc Natl Acad Sci U S A 113:E6669-E6678
Alvarez-Calderon, Francesca; Gregory, Mark A; Pham-Danis, Catherine et al. (2015) Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations. Clin Cancer Res 21:1360-72
Gardner, Lori A; Klawitter, Jelena; Gregory, Mark A et al. (2014) Inhibition of calcineurin combined with dasatinib has direct and indirect anti-leukemia effects against BCR-ABL1(+) leukemia. Am J Hematol 89:896-903
Alvarez-Calderon, Francesca; Gregory, Mark A; DeGregori, James (2013) Using functional genomics to overcome therapeutic resistance in hematological malignancies. Immunol Res 55:100-15
Gregory, Mark A; Phang, Tzu L; Neviani, Paolo et al. (2010) Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 18:74-87