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Blood. 2016 Jun 9;127(23):2890-902. doi: 10.1182/blood-2015-11-683581. Epub 2016 Apr 20.

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.

Author information

1
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
2
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
3
Division of Hematology and Hemostaseology, Department of Internal Medicine I, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
4
Department of Hematology and Oncology, Center for Internal Medicine II, Jena University Hospital, Jena, Germany;
5
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; and.
6
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.

PMID:
27099147
PMCID:
PMC4920675
DOI:
10.1182/blood-2015-11-683581
[Indexed for MEDLINE]
Free PMC Article

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