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

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

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12469-12474
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
StatePublished - Jul 13 2010

Fingerprint

Sirolimus
Growth
Autophagy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Protein Biosynthesis
mechanistic target of rapamycin complex 1
TOR complex 2
Phosphotransferases
Phosphorylation
Mutation
Survival
Therapeutics
Genes
OSI 027

Keywords

  • Cell proliferation
  • Cellular signaling
  • Kinase
  • mRNA translation
  • OSI-027

ASJC Scopus subject areas

  • General

Cite this

Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. / Carayol, Nathalie; Vakana, Eliza; Sassano, Antonella; Kaur, Surinder; Goussetis, Dennis J.; Glaser, Heather; Druker, Brian; Donato, Nicholas J.; Altman, Jessica K.; Barr, Sharon; Platanias, Leonidas C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 28, 13.07.2010, p. 12469-12474.

Research output: Contribution to journalArticle

Carayol, Nathalie ; Vakana, Eliza ; Sassano, Antonella ; Kaur, Surinder ; Goussetis, Dennis J. ; Glaser, Heather ; Druker, Brian ; Donato, Nicholas J. ; Altman, Jessica K. ; Barr, Sharon ; Platanias, Leonidas C. / Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 28. pp. 12469-12474.
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T1 - Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells

AU - Carayol, Nathalie

AU - Vakana, Eliza

AU - Sassano, Antonella

AU - Kaur, Surinder

AU - Goussetis, Dennis J.

AU - Glaser, Heather

AU - Druker, Brian

AU - Donato, Nicholas J.

AU - Altman, Jessica K.

AU - Barr, Sharon

AU - Platanias, Leonidas C.

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N2 - 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.

AB - 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.

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