CDK6 inactivation counteracts CALR-mutant-induced MPN evolution and sensitizes MPN stem cells to interferon-α treatment.

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.