PMID- 30587525 OWN - NLM STAT- MEDLINE DCOM- 20191108 LR - 20220317 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 133 IP - 11 DP - 2019 Mar 14 TI - Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. PG - 1171-1185 LID - 10.1182/blood-2018-08-870089 [doi] AB - 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. FAU - Beauchamp, Elspeth M AU - Beauchamp EM AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL. FAU - Abedin, Sameem M AU - Abedin SM AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. FAU - Radecki, Sara G AU - Radecki SG AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Fischietti, Mariafausta AU - Fischietti M AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Arslan, Ahmet Dirim AU - Arslan AD AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Blyth, Gavin T AU - Blyth GT AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Yang, Angela AU - Yang A AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Lantz, Connor AU - Lantz C AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Nelson, Alissa AU - Nelson A AD - Proteomics Center of Excellence, Northwestern University, Evanston, IL. FAU - Goo, Young Ah AU - Goo YA AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Proteomics Center of Excellence, Northwestern University, Evanston, IL. FAU - Akpan, Imo AU - Akpan I AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Eklund, Elizabeth A AU - Eklund EA AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL. FAU - Frankfurt, Olga AU - Frankfurt O AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. FAU - Fish, Eleanor N AU - Fish EN AD - Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; and. AD - Department of Immunology, University of Toronto, Toronto, ON, Canada. FAU - Thomas, Paul M AU - Thomas PM AUID- ORCID: 0000-0003-2887-4765 AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Proteomics Center of Excellence, Northwestern University, Evanston, IL. FAU - Altman, Jessica K AU - Altman JK AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL. FAU - Platanias, Leonidas C AU - Platanias LC AD - Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL. AD - Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL. LA - eng GR - R01 CA077816/CA/NCI NIH HHS/United States GR - I01 CX000916/CX/CSRD VA/United States GR - P41 GM108569/GM/NIGMS NIH HHS/United States GR - T32 GM008061/GM/NIGMS NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - R01 CA189074/CA/NCI NIH HHS/United States GR - R01 CA121192/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20181226 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Biomarkers, Tumor) RN - 0 (Proteome) RN - 0 (RNA, Messenger) RN - 04079A1RDZ (Cytarabine) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.22 (CDK9 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 9) SB - IM CIN - Blood. 2019 Mar 14;133(11):1167-1168. PMID: 30872269 MH - Animals MH - Antimetabolites, Antineoplastic/pharmacology MH - Apoptosis MH - Biomarkers, Tumor/metabolism MH - Carcinogenesis/*drug effects/metabolism/pathology MH - Cell Proliferation MH - Cyclin-Dependent Kinase 9/*antagonists & inhibitors/genetics/metabolism MH - Cytarabine/pharmacology MH - Humans MH - Leukemia, Myeloid, Acute/*drug therapy/genetics/metabolism/pathology MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Mechanistic Target of Rapamycin Complex 2/*metabolism MH - Mice MH - Mice, Nude MH - Phosphorylation MH - Protein Biosynthesis MH - Proteome/analysis MH - RNA, Messenger/drug effects/genetics/*metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC6418475 COIS- Conflict-of-interest disclosure: J.K.A. serves on a data safety and monitoring committee for GlycoMimetics and has served on advisory boards for Syros, Astellas, Janssen, Novartis, Seattle Genetics, Spectrum, Ariad, BMS, Immune Pharmaceuticals, Agios, and Celgene. The remaining authors declare no competing financial interests. EDAT- 2018/12/28 06:00 MHDA- 2019/11/09 06:00 PMCR- 2020/03/14 CRDT- 2018/12/28 06:00 PHST- 2018/08/21 00:00 [received] PHST- 2018/12/07 00:00 [accepted] PHST- 2018/12/28 06:00 [pubmed] PHST- 2019/11/09 06:00 [medline] PHST- 2018/12/28 06:00 [entrez] PHST- 2020/03/14 00:00 [pmc-release] AID - S0006-4971(20)42701-6 [pii] AID - 2019/870089 [pii] AID - 10.1182/blood-2018-08-870089 [doi] PST - ppublish SO - Blood. 2019 Mar 14;133(11):1171-1185. doi: 10.1182/blood-2018-08-870089. Epub 2018 Dec 26.