Protein kinase Cε inhibition restores megakaryocytic differentiation of hematopoietic progenitors from primary myelofibrosis patients

Abstract

Among the three classic Philadelphia chromosome-negative myeloproliferative neoplasms, primary myelofibrosis (PMF) is the most severe in terms of disease biology, survival and quality of life. Abnormalities in the process of differentiation of PMF megakaryocytes (MKs) are a hallmark of the disease. Nevertheless, the molecular events that lead to aberrant megakaryocytopoiesis have yet to be clarified. Protein kinase Cε (PKCε) is a novel serine/threonine kinase that is overexpressed in a variety of cancers, promoting aggressive phenotype, invasiveness and drug resistance. Our previous findings on the role of PKCε in normal (erythroid and megakaryocytic commitment) and malignant (acute myeloid leukemia) hematopoiesis prompted us to investigate whether it could be involved in the pathogenesis of PMF MK-impaired differentiation. We demonstrate that PMF megakaryocytic cultures express higher levels of PKCε than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKCε function (by a negative regulator of PKCε translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKCε-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKCε directly affects the PMF neoplastic clone and represent a proof-of-concept for PKCε inhibition as a novel therapeutic strategy in PMF.