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Pediatric mastocytosis–associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations

Abstract : 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 D816V 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.
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https://hal-amu.archives-ouvertes.fr/hal-03623808
Contributor : François Bertucci Connect in order to contact the contributor
Submitted on : Tuesday, March 29, 2022 - 7:34:45 PM
Last modification on : Wednesday, March 30, 2022 - 3:59:56 AM

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ying yang, Sébastien Létard, Laurence Borge, Amandine Chaix, Katia Hanssens, et al.. Pediatric mastocytosis–associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations. Blood, American Society of Hematology, 2010, 116 (7), pp.1114-1123. ⟨10.1182/blood-2009-06-226027⟩. ⟨hal-03623808⟩

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