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Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood 2019 Mar 14;133(11):1171-1185

Date

12/28/2018

Pubmed ID

30587525

Pubmed Central ID

PMC6418475

DOI

10.1182/blood-2018-08-870089

Scopus ID

2-s2.0-85062974965   18 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.

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 LC

Author

Sameem Abedin MD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antimetabolites, 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