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Protein kinase Cɛ inhibition restores megakaryocytic differentiation of hematopoietic progenitors from primary myelofibrosis patients.
Masselli, E; Carubbi, C; Gobbi, G; Mirandola, P; Galli, D; Martini, S; Bonomini, S; Crugnola, M; Craviotto, L; Aversa, F; Vitale, M.
Afiliación
  • Masselli E; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
  • Carubbi C; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Gobbi G; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Mirandola P; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Galli D; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Martini S; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Bonomini S; Unit of Human Anatomy and Histology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy.
  • Crugnola M; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
  • Craviotto L; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
  • Aversa F; Department of Clinical and Experimental Medicine, Hematology and BMT Unit, University of Parma, Parma, Italy.
  • Vitale M; Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Leukemia ; 29(11): 2192-201, 2015 Nov.
Article en En | MEDLINE | ID: mdl-26183534
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Asunto principal: Megacariocitos / Inhibidores de Proteínas Quinasas / Proteína Quinasa C-epsilon / Mielofibrosis Primaria Tipo de estudio: Etiology_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2015 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Asunto principal: Megacariocitos / Inhibidores de Proteínas Quinasas / Proteína Quinasa C-epsilon / Mielofibrosis Primaria Tipo de estudio: Etiology_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2015 Tipo del documento: Article País de afiliación: Italia