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, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1171-1185
Number of pages15
JournalBlood
Volume133
Issue number11
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Beauchamp, E. M., Abedin, S. M., Radecki, S. G., Fischietti, M., Arslan, A. DI., Blyth, G. T., Yang, A., Lantz, C., Nelson, A., Goo, Y. A., Akpan, I., Eklund, E. A., Frankfurt, O., Fish, E. N., Thomas, P. M., Altman, J. K., & Platanias, L. C. (2019). Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood, 133(11), 1171-1185. https://doi.org/10.1182/blood-2018-08-870089