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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01245

Phosphoproteomic landscaping identifies non-canonical cKIT signaling in Polycythemia Vera erythroid progenitors

 Giulia Federici1,  Lilian Varricchio2,  Fabrizio Martelli3,  Mario Falchi4,  Orietta Picconi4,  Federica Francescangeli5, Paola Contavalli6, Gabriella Girelli7, Agostino Tafuri8, Emanuel Petricoin III9,  Ann Zeuner6 and  Anna Rita Migliaccio10*
  • 1Regina Elena National Cancer Institute, Italy
  • 2The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, United States
  • 3National Center for Preclinical and Clinical Research and Evaluation of Pharmaceutical Drugs, National Institute of Health (ISS), Italy
  • 4National HIV/AIDS Center, National Institute of Health (ISS), Italy
  • 5Department of Oncology and Molecular Medicine, National Institute of Health, Italy
  • 6Dipartimento Oncologia e Medicina Molecolare, National Institute of Health (ISS), Italy
  • 7Immunohematology and Transfusion Medicine Unit, Sapienza University of Rome, Italy
  • 8Department of Clinic and Molecular Medicine - Sant’Andrea Hospital, Sapienza University of Rome, Italy
  • 9Center for Applied Proteomics and Molecular Medicine, George Mason University, United States
  • 10Tich Cancer Institute, Icahn School of Medicine at Mount Sinai, United States

Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signalling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB) and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB respectively activated transient or sustained canonical cKIT-signalling, PV showed a non-canonical signalling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signalling/metabolism that may contribute to the great erythroid output occurring during development and in PV.

Keywords: Stem Cell Factor, CKIT, Erythropoiesis, Polycythemia Vera, Erythroid progenitors

Received: 02 Aug 2019; Accepted: 29 Oct 2019.

Copyright: © 2019 Federici, Varricchio, Martelli, Falchi, Picconi, Francescangeli, Contavalli, Girelli, Tafuri, Petricoin III, Zeuner and Migliaccio. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Anna Rita Migliaccio, Icahn School of Medicine at Mount Sinai, Tich Cancer Institute, New York, 10029, NY, United States, annarita.migliaccio@unibo.it