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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cyclin-Dependent Kinase 6 / pharmacology*
  • Humans
  • Janus Kinase 2 / genetics*
  • Mutation*
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / etiology*
  • Myeloproliferative Disorders / mortality
  • Myeloproliferative Disorders / pathology
  • NF-kappa B / metabolism*
  • Neoplasms
  • Signal Transduction


  • NF-kappa B
  • JAK2 protein, human
  • Janus Kinase 2
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6