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.