Identification and targeting of novel CDK9 complexes in acute myeloid leukemia
| Autor: | Olga Frankfurt, Gavin T. Blyth, Connor Lantz, Eleanor N. Fish, Leonidas C. Platanias, Ahmet Dirim Arslan, Mariafausta Fischietti, Elspeth M. Beauchamp, Young Ah Goo, Elizabeth A. Eklund, Jessica K. Altman, Paul M. Thomas, Angela Yang, Imo Akpan, Sameem Abedin, Alissa Nelson, Sara G. Radecki |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Scaffold protein Antimetabolites Antineoplastic Proteome Carcinogenesis Immunology Mice Nude Apoptosis Mechanistic Target of Rapamycin Complex 2 Mechanistic Target of Rapamycin Complex 1 Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Biomarkers Tumor Tumor Cells Cultured Protein biosynthesis Animals Humans RNA Messenger Phosphorylation MLST8 PI3K/AKT/mTOR pathway Cell Proliferation Chemistry TOR Serine-Threonine Kinases Cytarabine Myeloid leukemia Cell Biology Hematology Cyclin-Dependent Kinase 9 Xenograft Model Antitumor Assays Leukemia Myeloid Acute 030104 developmental biology Protein Biosynthesis 030220 oncology & carcinogenesis Cancer research Cyclin-dependent kinase 9 Signal transduction BLOOD Commentary Signal Transduction |
| Zdroj: | Blood. 133:1171-1185 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2018-08-870089 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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