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Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood 2019 Mar 14;133(11):1171-1185 PMID: 30587525 PMCID: PMC6418475

Pubmed ID

30587525

DOI

10.1182/blood-2018-08-870089

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 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.

Author List

Beauchamp EM, Abedin SM, Radecki SG, Fischietti M, Arslan AD, Blyth GT, Yang A, Lantz C, Nelson A, Goo YA, Akpan I, Eklund EA, Frankfurt O, Fish EN, Thomas PM, Altman JK, Platanias LC

Author

Sameem Abedin MD Assistant Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-85062974965
jenkins-FCD Prod-331 a335b1a6d1e9c32173c9534e6f6ff51494143916