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Cdk6 coordinates Jak2V617F mutant MPN via NFκB 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 NFκB), activating LSCs and preventing apoptosis in a kinase-independent manner.

Abstract

Over 80% of patients with myeloproliferative neoplasms (MPNs) harbour 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 three hallmarks of disease: besides regulating malignant stem cell quiescence, it promotes NFκB 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.