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Blood. 2018 Dec 26. pii: blood-2018-08-870089. doi: 10.1182/blood-2018-08-870089. [Epub ahead of print]

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia.

Author information

1
Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States.
2
Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.
3
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
4
Proteomics Center of Excellence, Northwestern University, Evanston, IL, United States.
5
Toronto General Hospital Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON, Canada.
6
Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States; l-platanias@northwestern.edu.

Abstract

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 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 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 anti-leukemic responses in AML xenografts in vivo.

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