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CDK6 coordinates JAK2V617F mutant MPN via NF-κB and apoptotic networks

Iris Z. Uras, Barbara Maurer, Harini Nivarthi, Philipp Jodl, Karoline Kollmann, Michaela Prchal-Murphy, Jelena D. Milosevic Feenstra, Markus Zojer, Sabine Lagger, Reinhard Grausenburger, Beatrice Grabner, Raimund Holly, Anoop Kavirayani, Christoph Bock, Heinz Gisslinger, Peter Valent, Robert Kralovics and Veronika Sexl

Key Points

  • The absence of Cdk6 ameliorates MPN hallmarks, lessens splenomegaly, and enhances survival of JAK2V617F mice.

  • CDK6 facilitates MPN by enhancing cytokine production (in conjunction with NF-κB), activating leukemic stem cells and preventing apoptosis.

Abstract

Over 80% of patients with myeloproliferative neoplasms (MPNs) harbor the acquired somatic JAK2V617F 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.

  • Submitted August 31, 2018.
  • Accepted January 7, 2019.
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