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

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dc.contributor.authorMenzl, I.
dc.contributor.authorZhang, T.
dc.contributor.authorBerger-Becvar, A.
dc.contributor.authorGrausenburger, R.
dc.contributor.authorHeller, G.
dc.contributor.authorPrchal-Murphy, M.
dc.contributor.authorEdlinger, L.
dc.contributor.authorKnab, V.M.
dc.contributor.authorUras, I.Z.
dc.contributor.authorGrundschober, E.
dc.contributor.authorBauer, K.
dc.contributor.authorRoth, M.
dc.contributor.authorSkucha, A.
dc.contributor.authorLiu, Y.
dc.contributor.authorHatcher, J.M.
dc.contributor.authorLiang, Y.
dc.contributor.authorKwiatkowski, N.P.
dc.contributor.authorFux, D.
dc.contributor.authorHoelbl-Kovacic, A.
dc.contributor.authorKubicek, S.
dc.contributor.authoret al.
dc.date.issued2019
dc.description.abstractCyclin-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.
dc.description.statementofresponsibilityIngeborg Menzl ... Junia V. Melo ... et al.
dc.identifier.citationNature Communications, 2019; 10(1):4741-1-4741-15
dc.identifier.doi10.1038/s41467-019-12656-x
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.orcidMelo, J.V. [0009-0009-5343-4893]
dc.identifier.urihttps://hdl.handle.net/2440/145222
dc.language.isoen
dc.publisherNature Portfolio
dc.rights© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41467-019-12656-x
dc.subjectCancer therapy; Haematological cancer
dc.subject.meshCell Line, Tumor
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Inbred NOD
dc.subject.meshMice, Transgenic
dc.subject.meshMice, Knockout
dc.subject.meshHumans
dc.subject.meshMice, SCID
dc.subject.meshDisease Models, Animal
dc.subject.meshFusion Proteins, bcr-abl
dc.subject.meshProtein Kinase Inhibitors
dc.subject.meshSignal Transduction
dc.subject.meshCell Survival
dc.subject.meshPrecursor B-Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.meshSmall Molecule Libraries
dc.subject.meshCyclin-Dependent Kinase 8
dc.subject.meshTOR Serine-Threonine Kinases
dc.titleA kinase-independent role for CDK8 in BCR-ABL1+ leukemia.
dc.typeJournal article
pubs.publication-statusPublished

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