AUTHOR=Federici Giulia , Varricchio Lilian , Martelli Fabrizio , Falchi Mario , Picconi Orietta , Francescangeli Federica , Contavalli Paola , Girelli Gabriella , Tafuri Agostino , Petricoin Emanuel F. , Mazzarini Maria , Zeuner Ann , Migliaccio Anna Rita TITLE=Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors JOURNAL=Frontiers in Oncology VOLUME=9 YEAR=2019 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01245 DOI=10.3389/fonc.2019.01245 ISSN=2234-943X 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.