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Chronic myleproliferative neoplasms

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

Leukemia volume 29, pages 2192–2201 (2015)Cite this article

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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.

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Acknowledgements

This work was supported by Programma di ricerca-Area1 Regione Emilia-Romagna-Università (ER-Università) 2010–2012 to GG and Finanziamento italiano per la Ricerca di Base (FIRB)-accordo di programma 2010 (RBAP10KCNS_002) to MV. EM was supported by AIL (Italian Association against Leukemia). We are grateful to Professor F Quaini, University of Parma, for providing cells from PMF3, and to Professor AM Vannucchi, University of Florence, for providing cells from PMF1 and 5.

Author contributions

EM, GG, PM, FA and MV designed the research, analyzed data and wrote the manuscript. EM, CC, SM, DG and SB performed experiments. MC, LC and FA provided patients’ samples and data.

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Authors and Affiliations

  1. Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    E Masselli, S Bonomini, M Crugnola & F Aversa

  2. Department of Biomedical, Unit of Human Anatomy and Histology, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, Parma, Italy

    E Masselli, C Carubbi, G Gobbi, P Mirandola, D Galli, S Martini & M Vitale

  3. Department of Clinical and Experimental Medicine, Hematology and BMT Unit, University of Parma, Parma, Italy

    L Craviotto & F Aversa

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  1. E Masselli
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Correspondence to M Vitale.

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Masselli, E., Carubbi, C., Gobbi, G. et al. Protein kinase Cɛ inhibition restores megakaryocytic differentiation of hematopoietic progenitors from primary myelofibrosis patients. Leukemia 29, 2192–2201 (2015). https://doi.org/10.1038/leu.2015.150

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