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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1245
JournalFrontiers in Oncology
Volume9
DOIs
Publication statusPublished - 2019

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