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Published on: August 3, 2017
CDK6 coordinates JAK2 V617F mutant MPN via NF-κB and apoptotic networks
Iris Z Uras1, Barbara Maurer1, Harini Nivarthi2
1Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 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.
Insights
Targeting CDK6 offers a novel therapeutic strategy for myeloproliferative neoplasms (MPNs). Its absence improves survival and reduces disease symptoms by impacting stem cell quiescence, NF-κB signaling, and apoptosis.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Myeloproliferative neoplasms (MPNs) are often driven by the JAK2 V617F mutation.
- Current JAK inhibitor therapies for MPNs lack curative potential and sustained response.
- There is a critical need for novel therapeutic strategies targeting MPN pathogenesis.
Purpose of the Study:
- To investigate the role of Cyclin-Dependent Kinase 6 (CDK6) in the evolution of MPNs.
- To evaluate CDK6 as a potential therapeutic target for MPN treatment.
Main Methods:
- Analysis of Cdk6 function in MPN models.
- Assessment of CDK6 protein's impact on malignant stem cell quiescence, NF-κB signaling, and apoptosis.
- Comparison of CDK6 functions with palbociclib, a CDK4/6 inhibitor.
Main Results:
- Absence of Cdk6 significantly ameliorates clinical symptoms and prolongs survival in MPN models.
- CDK6 regulates malignant stem cell quiescence, promotes NF-κB signaling, enhances cytokine production, and inhibits apoptosis.
- CDK6's pathogenic functions in MPNs are largely independent of its kinase activity, as shown by palbociclib's ineffectiveness.
Conclusions:
- CDK6 plays a critical role in MPN pathogenesis through kinase-independent mechanisms.
- Targeting CDK6 presents a promising novel therapeutic approach for patients with MPNs.
- These findings provide a strong rationale for developing CDK6-specific therapies for MPNs.
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