RESUMEN
Mastocytosis is a rare and chronic disease with phenotypes ranging from indolent to severe. Prognosis for this disease is variable and very few biomarkers to predict disease evolution or outcome are currently known. We have performed comprehensive screening in our large cohort of mastocytosis patients for mutations previously found in other myeloid diseases and that could serve as prognostic indicators. KIT, SRSF2-P95 and TET2 mutations were by far the most frequent, detected in 81%, 24% and 21% of patients, respectively. Where TET2 and SRSF2-P95 mutation both correlated with advanced disease phenotypes, SRSF2-P95 hotspot mutation was found almost exclusively in patients diagnosed with associated clonal hematologic non-mast cell disease. Statistically, TET2 and SRSF2-P95 mutations were highly associated, suggesting a mechanistic link between these two factors. Finally, analysis of both clonal and sorted cell populations from patients confirms the presence of these mutations in the mast cell component of the disease, suggests an ontological mutation hierarchy and provides evidence for the expansion of multiple clones. This highlights the prognostic potential of such approaches, if applied systematically, for delineating the roles of specific mutations in predisposing and/or driving distinct disease phenotypes.
Asunto(s)
Epigénesis Genética , Mastocitosis/genética , Mastocitosis/patología , Mutación , Proteínas Nucleares/genética , Ribonucleoproteínas/genética , Evolución Clonal/genética , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Humanos , Masculino , Mastocitos/metabolismo , Mastocitos/patología , Mastocitosis/mortalidad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit/genética , Factores de Empalme Serina-ArgininaRESUMEN
Although a role for oncogenic KIT in driving mast cell disease is clear, the mechanisms driving the multiple phenotypic and clinical manifestations of this disorder are not well elucidated. We now show, using a large cohort of mastocytosis patients, including an almost equal number of aggressive and nonaggressive cases of systemic mastocytosis, that in contrast to the oncogenic KITD816V, TET2 mutation statistically associates with aggressive forms of the disease. By infecting primary murine bone marrow-derived mast cells with KITD816V, we also observe a significant and competitive growth advantage for KITD816V in Tet2-nullizygous compared with wild-type cells. TET2-deficient cells display increased proliferation and can survive in the absence of cytokines. Taken together, these data demonstrate a oncogenic cooperation in mast cells and reveal TET2 mutation as a potential marker to diagnose and predict severe forms of mastocytosis.
