1. Identification and targeting of novel CDK9 complexes in acute myeloid leukemia.
- Author
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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, and Platanias LC
- Subjects
- Animals, Antimetabolites, Antineoplastic pharmacology, Apoptosis, Biomarkers, Tumor metabolism, Carcinogenesis metabolism, Carcinogenesis pathology, Cell Proliferation, Cyclin-Dependent Kinase 9 genetics, Cyclin-Dependent Kinase 9 metabolism, Cytarabine pharmacology, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mice, Mice, Nude, Phosphorylation, Protein Biosynthesis, Proteome analysis, RNA, Messenger drug effects, RNA, Messenger genetics, Signal Transduction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Carcinogenesis drug effects, Cyclin-Dependent Kinase 9 antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 2 metabolism, RNA, Messenger metabolism, TOR Serine-Threonine Kinases metabolism
- 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.
- Published
- 2019
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