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Publication type: Journal Article
Document type: Full Paper

Year: 2019

Author(s): Menzl, I; Zhang, T; Berger-Becvar, A; Grausenburger, R; Heller, G; Prchal-Murphy, M; Edlinger, L; Knab, VM; Uras, IZ; Grundschober, E; Bauer, K; Roth, M; Skucha, A; Liu, Y; Hatcher, JM; Liang, Y; Kwiatkowski, NP; Fux, D; Hoelbl-Kovacic, A; Kubicek, S; Melo, JV; Valent, P; Weichhart, T; Grebien, F; Zuber, J; Gray, NS; Sexl, V

Title: A kinase-independent role for CDK8 in BCR-ABL1+ leukemia.

Source: Nat Commun. 2019; 10(1):4741



Authors Vetmeduni Vienna:

Berger-Becvar Angelika
Edlinger Leo
Fux Daniela
Grausenburger Reinhard
Grebien Florian
Grundschober Eva
Hölbl-Kovacic Andrea
Knab Vanessa-Maria
Menzl Ingeborg
Prchal-Murphy Michaela
Sexl Veronika
Uras Jodl Iris

Vetmed Research Units
Institute for Medical Biochemistry
Institute of Pharmacology and Toxicology


Project(s): Stat1ioning Irf1 in mammary tumorigenesis and therapy response

CDK 8 a weapon to arm NK cells against leukemia


Abstract:
Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.


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