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.
|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|