CDK6 Is a Therapeutic Target in Myelofibrosis.

ABSTRACT

Myelofibrosis (myelofibrosis) is a deadly blood neoplasia with the worst prognosis among myeloproliferative neoplasms (MPN). The JAK2 inhibitors ruxolitinib and fedratinib have been approved for treatment of myelofibrosis, but they do not offer significant improvement of bone marrow fibrosis. CDK6 expression is significantly elevated in MPN/myelofibrosis hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor palbociclib alone or in combination with ruxolitinib in Jak2V617F and MPLW515L murine models of myelofibrosis. Treatment with palbociclib alone significantly reduced leukocytosis and splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of myelofibrosis. Combined treatment of palbociclib and ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size, and abrogation of bone marrow fibrosis in murine models of myelofibrosis. Palbociclib treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, treatment with palbociclib or depletion of CDK6 inhibited Aurora kinase, NF-κB, and TGFß signaling pathways in Jak2V617F mutant hematopoietic cells and attenuated expression of fibrotic markers in the bone marrow. Overall, these data suggest that palbociclib in combination with ruxolitinib may have therapeutic potential for treatment of myelofibrosis and support the clinical investigation of this drug combination in patients with myelofibrosis. SIGNIFICANCE: These findings demonstrate that CDK6 inhibitor palbociclib in combination with ruxolitinib ameliorates myelofibrosis, suggesting this drug combination could be an effective therapeutic strategy against this devastating blood disorder.