Journal Article

Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells

Kaur, Surinder, Goussetis, Dennis J., Glaser, Heather, Altman, Jessica K., Vakana, Eliza, Donato, Nicholas J., Druker, Brian J., Platanias, Leonidas C., Carayol, Nathalie, Sassano, Antonella, Stark, George R., Barr, Sharon

2010

Overview

mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37/46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2/mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Ph+ ALL.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Antibodies / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / autophagy / Biological Sciences / Cell growth / Cells / Cellular Structures - metabolism / Chronic myeloid leukemia / Fusion Proteins, bcr-abl - antagonists & inhibitors / Fusion Proteins, bcr-abl - genetics / Fusion Proteins, bcr-abl - metabolism / Gene expression / genes / Humans / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - pharmacology / Intracellular Signaling Peptides and Proteins - therapeutic use / K562 cells / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Medical treatment / Messenger RNA / Mesylates / Mutation / Mutation - drug effects / patients / Phosphorylation / Phosphorylation - drug effects / Progenitor cells / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - pharmacology / Protein-Serine-Threonine Kinases - therapeutic use / Signal transduction / Signal Transduction - drug effects / Signal Transduction - genetics / Sirolimus - pharmacology / Sirolimus - therapeutic use / TOR Serine-Threonine Kinases / translation (genetics)