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