Frontiers in Oncology (Nov 2019)

Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors

  • Giulia Federici,
  • Lilian Varricchio,
  • Fabrizio Martelli,
  • Mario Falchi,
  • Orietta Picconi,
  • Federica Francescangeli,
  • Paola Contavalli,
  • Gabriella Girelli,
  • Agostino Tafuri,
  • Emanuel F. Petricoin,
  • Maria Mazzarini,
  • Ann Zeuner,
  • Anna Rita Migliaccio

DOI
https://doi.org/10.3389/fonc.2019.01245
Journal volume & issue
Vol. 9

Abstract

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Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling 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-signaling, PV showed a non-canonical signaling 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 signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.

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