Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood 2019 Mar 14;133(11):1171-1185
Date
12/28/2018Pubmed ID
30587525Pubmed Central ID
PMC6418475DOI
10.1182/blood-2018-08-870089Scopus ID
2-s2.0-85062974965 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
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, Platanias LCAuthor
Sameem Abedin MD Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntimetabolites, Antineoplastic
Apoptosis
Biomarkers, Tumor
Carcinogenesis
Cell Proliferation
Cyclin-Dependent Kinase 9
Cytarabine
Humans
Leukemia, Myeloid, Acute
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Mice, Nude
Phosphorylation
Protein Biosynthesis
Proteome
RNA, Messenger
Signal Transduction
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
