Advertisement

Identification and targeting of novel CDK9 complexes in acute myeloid leukemia

Elspeth M. Beauchamp, Sameem M. Abedin, Sara G. Radecki, Mariafausta Fischietti, Ahmet Dirim Arslan, Gavin T. Blyth, Angela Yang, Connor Lantz, Alissa Nelson, Young Ah Goo, Imo Akpan, Elizabeth A. Eklund, Olga Frankfurt, Eleanor N. Fish, Paul M. Thomas, Jessica K. Altman and Leonidas C. Platanias

Key points

  • CDK9 exhibits differential binding to distinct cellular elements of mTOR complexes and forms CDK9-mTOR like-complexes (CTORC1 and CTORC2).

  • CTORC1 controls transcription of genes important for leukemogenesis, while CTORC2 controls mRNA translation.

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.

  • Submitted August 21, 2018.
  • Accepted December 7, 2018.