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

Media type: E-Article

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

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

imprint: American Society of Hematology, 2019

Language: English

DOI: 10.1182/blood-2018-08-872648

ISSN: 0006-4971; 1528-0020

Origination:

Footnote:

Description: 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.

Access State: Open Access

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