title: Diverse mechanisms of mTOR activation in chronic and blastic phase of chronic myelogenous leukemia.
abstract: Chronic myelogenous leukemia (CML) is a stem cell disorder, and leukemia stem cells (LSCs) can contribute to the relapse of the disease. Quiescent LSCs are BCR-ABL independent and resistant to imatinib; therefore, there is an unmet need to identify new therapeutic targets in LSCs. Inhibition of the mammalian target of rapamycin (mTOR) in imatinib-resistant BCR-ABL1-positive cells was effective in vitro, but in a pilot clinical trial, only a few patients responded to the treatment. In this study, we demonstrate that mTOR activation in CML CD34(+) progenitor cells is ERK dependent in chronic phase of the disease and ERK independent in blast crisis. Rapamycin effectively inhibits mTOR in all phases of CML, but does not reduce number of LSC-enriched CD34(+) blast crisis (BC) cells, neither alone nor in combination with imatinib in CML-BC cells. These results show that potential therapeutic benefits of mTOR inhibition may be the result of effects on differentiated leukemic cells and may be potentially achieved only in the chronic phase of the disease.
authors: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors: Tomasz
authors: T
authors: Stoklosa
authors: Eliza
authors: E
authors: Glodkowska-Mrowka
authors: Grazyna
authors: G
authors: Hoser
authors: Magdalena
authors: M
authors: Kielak
authors: Ilona
authors: I
authors: Seferynska
authors: Pawel
authors: P
authors: Wlodarski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C546842:MTOR protein, human; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus