title: Protein kinase Cɛ 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 Cɛ (PKCɛ) 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 PKCɛ 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 PKCɛ than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKCɛ function (by a negative regulator of PKCɛ translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKCɛ-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKCɛ directly affects the PMF neoplastic clone and represent a proof-of-concept for PKCɛ inhibition as a novel therapeutic strategy in PMF.
authors.affiliation: Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.|Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Masselli
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carubbi
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Mirandola
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Galli
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Martini
authors.affiliation: Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bonomini
authors.affiliation: Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Crugnola
authors.affiliation: Department of Clinical and Experimental Medicine, Hematology and BMT Unit, University of Parma, Parma, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Craviotto
authors.affiliation: Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.|Department of Clinical and Experimental Medicine, Hematology and BMT Unit, University of Parma, Parma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology*; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D051744:Protein Kinase C-epsilon