4.7 Article

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

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LEUKEMIA
卷 29, 期 11, 页码 2192-2201

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DOI: 10.1038/leu.2015.150

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  1. Programma di ricerca-Area1 Regione Emilia-Romagna-Universita (ER-Universita)
  2. Finanziamento italiano per la Ricerca di Base (FIRB)-accordo di programma [RBAP10KCNS_002]
  3. AIL (Italian Association against Leukemia)

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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 C epsilon (PKC epsilon) 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 PKC epsilon 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 PKC epsilon than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKC epsilon function (by a negative regulator of PKC epsilon translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKC epsilon-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKC epsilon directly affects the PMF neoplastic clone and represent a proof-of-concept for PKC epsilon inhibition as a novel therapeutic strategy in PMF.

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