Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-07, Vol.107 (28), p.12469-12474

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.