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Blood. 2019 Apr 11;133(15):1677-1690. doi: 10.1182/blood-2018-08-872648. Epub 2019 Jan 11.

CDK6 coordinates JAK2 V617F mutant MPN via NF-κB and apoptotic networks.

Author information

1
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
3
Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienna, Vienna, Austria.
4
Institute of Pathology and Forensic Veterinary Medicine, University of Veterinary Medicine, Vienna, Austria.
5
Vienna Biocenter Core Facilities, Histopathology Facility, Vienna, Austria; and.
6
Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Abstract

Over 80% of patients with myeloproliferative neoplasms (MPNs) harbor the acquired somatic JAK2 V617F mutation. JAK inhibition is not curative and fails to induce a persistent response in most patients, illustrating the need for the development of novel therapeutic approaches. We describe a critical role for CDK6 in MPN evolution. The absence of Cdk6 ameliorates clinical symptoms and prolongs survival. The CDK6 protein interferes with 3 hallmarks of disease: besides regulating malignant stem cell quiescence, it promotes nuclear factor κB (NF-κB) signaling and contributes to cytokine production while inhibiting apoptosis. The effects are not mirrored by palbociclib, showing that the functions of CDK6 in MPN pathogenesis are largely kinase independent. Our findings thus provide a rationale for targeting CDK6 in MPN.

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