Abstract Interferon‐α (IFNα) remains a potent therapeutic option for myeloproliferative neoplasms (MPNs) with an activated JAK/STAT signaling axis. However, variable patient responses highlight the need for optimized combination strategies. Recent studies suggest a link between cyclin‐dependent kinase 6 (CDK6) and IFN signaling. Here, we investigated whether CDK6 inhibition might play a role in IFN responsiveness in MPN cells. Using CALR del52 knockin mice, we observed that genetic ablation of Cdk6 resulted in a reduction of spleen weight and platelet counts, while concurrently inducing interferon‐associated transcriptional programs and upregulation of interferon‐alpha receptor 1 (IFNAR1) on MPN cells. CDK6‐deficient CALR del52 hematopoietic stem and progenitor cells (HSPCs) exhibited increased apoptosis and reduced proliferation upon inflammatory challenge compared to wild‐type CALR del52 cells, positioning CDK6 as a brake on IFN signaling. Pharmacologic inhibition of CDK6 using palbociclib synergized with pegylated IFNα (pegIFNα), resulting in growth inhibition of MPN cells in vitro and in vivo . In MPN patient samples, lower CDK6 expression was associated with increased IFNAR1 expression and with stronger responses to the palbociclib/pegIFNα combination. Importantly, dose reduction of both palbociclib and pegIFNα maintained efficacy in MPN samples while minimizing cytotoxicity in control hematopoietic cells, revealing a favorable therapeutic window. These findings highlight the potential of combining CDK6 inhibition with pegIFNα to enhance anti‐neoplastic effects in MPNs and support a novel potential approach to improve MPN therapy.
Ringhofer et al. (Fri,) studied this question.