title: BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells.
abstract: Chronic myelogenous leukemia (CML) results from malignant transformation of a primitive hematopoietic cell by the BCR/ABL oncogene. The breakpoint cluster region/ABL (BCR/ABL) tyrosine kinase inhibitor imatinib mesylate (imatinib) is highly effective in inducing remissions in CML. However, the effects of imatinib on intracellular signaling in primary progenitor cells are not well described. We show that imatinib exposure resulted in a significant dose-responsive reduction in BCR/ABL kinase activity in CML CD34+ cells. However, imatinib treatment resulted in an increase in activity of p42/44 mitogen-activated protein kinase (MAPK), an important downstream effector of BCR/ABL. Increased MAPK activity was growth factor dependent. Pharmacologic inhibition of MAPK using MAPK/extracellular signal-regulated kinase kinase-1/2 (MEK-1/2) inhibitors significantly reduced CML progenitor proliferation. Combined treatment with a MEK-1/2 inhibitor and imatinib significantly increased suppression of CML progenitors compared with either inhibitor alone. In contrast, imatinib treatment resulted in a small reduction in AKT activity. Combined treatment with a phosphatidylinositol-3 (PI-3) kinase inhibitor and imatinib significantly increased suppression of CML progenitor growth compared with either inhibitor alone. We conclude that inhibition of BCR/ABL kinase activity in CML progenitors by imatinib results in a growth factor-dependent compensatory increase in MAPK activity and in only partial inhibition of PI-3 kinase activity. These mechanisms may contribute to incomplete elimination of CML progenitors by imatinib.
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.forename: Melissa
authors.initials: M
authors.lastname: Holtz
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases