title: Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations.
abstract: Compared with adults, pediatric mastocytosis has a relatively favorable prognosis. Interestingly, a difference was also observed in the status of c-kit mutations according to the age of onset. Although most adult patients have a D(816)V mutation in phosphotransferase domain (PTD), we have described that half of the children carry mutations in extracellular domain (ECD). KIT-ECD versus KIT-PTD mutants were introduced into rodent Ba/F3, EML, Rat2, and human TF1 cells to investigate their biologic effect. Both ECD and PTD mutations induced constitutive receptor autophosphorylation and ligand-independent proliferation of the 3 hematopoietic cells. Unlike ECD mutants, PTD mutants enhanced cluster formation and up-regulated several mast cell-related antigens in Ba/F3 cells. PTD mutants failed to support colony formation and erythropoietin-mediated erythroid differentiation. ECD and PTD mutants also displayed distinct whole-genome transcriptional profiles in EML cells. We observed differences in their signaling properties: they both activated STAT, whereas AKT was only activated by ECD mutants. Consistently, AKT inhibitor suppressed ECD mutant-dependent proliferation, clonogenicity, and erythroid differentiation. Expression of myristoylated AKT restored erythroid differentiation in EML-PTD cells, suggesting the differential role of AKT in those mutants. Overall, our study implied different pathogenesis of pediatric versus adult mastocytosis, which might explain their diverse phenotypes.
authors.affiliation: INSERM U891, Centre de Recherche en Cancérologie de Marseille, Laboratoire de Signalisation, Hématopoïèse et Mécanisme de l'Oncogenèse, Centre de Référence des Mastocytoses-CEREMAST Institut Paoli-Calmettes, 27 Boulevard Leï Roure, Marseille, France.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Sébastien
authors.initials: S
authors.lastname: Létard
authors.forename: Laurence
authors.initials: L
authors.lastname: Borge
authors.forename: Amandine
authors.initials: A
authors.lastname: Chaix
authors.forename: Katia
authors.initials: K
authors.lastname: Hanssens
authors.forename: Sophie
authors.initials: S
authors.lastname: Lopez
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Sophie
authors.initials: S
authors.lastname: Gomez
authors.forename: Paulo
authors.initials: P
authors.lastname: de Sepulveda
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D008415:Mastocytosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D010770:Phosphotransferases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt