Journal
BLOOD
Volume 133, Issue 11, Pages 1171-1185Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-08-870089
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Funding
- National Institutes of Health, National Cancer Institute (NCI) [CA121192, CA77816, CA189074]
- Department of Veterans Affairs [I01CX000916]
- Lurie Cancer Center Flow Cytometry Core Facility
- Northwestern Proteomics Core Facility via the Robert H. Lurie Comprehensive Cancer Center Support grant [NCI CA060553]
- Vassilatos Foundation
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Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8. Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6. Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.
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