SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes

Abstract

International audienceMastocytosis 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

Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications

“…28 SRSF2 mutations has been described in 47% of chronic myelomonocytic leukemia 29 and, although less frequently, in other types of myelodysplastic and myeloproliferative neoplasms. [30][31][32] All neutrophilic post-polycythemic myelofibrosis cases showed only wild-type alleles for these genes, a finding that suggests that the neutrophilic proliferation arising during the fibrotic stages of polycythemia vera is caused by mechanisms biologically distinct from those involved in chronic neutrophilic leukemia or atypical chronic myeloid leukemia.…”

Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice

“…25 The frequency of SF3B1 mutations in AdvSM is low, ranging from 0 to 5%. 64,65 U2AF1 mutations are less frequently reported in SM. 64,65 The gene ASXL1 (additional sex combs-like 1) encodes for a protein of the polycomb group and trithorax complex family, which interacts with retinoic acid receptor and may be involved in chromatin remodeling.…”

“…74 Mutations in the spliceosome machinery have recently been identified using whole exome/genome technologies in MDS and MPN. 75 A mutation in the hotspot region of SRSF2 (codon P95) is found in approximately 1/3 of AdvSM patients 64,65 but is usually not detectable in patients with ISM or SSM. 25 It is more common in ASM-AHN 25,64,65 and precedes KIT D816V in these patients.…”

“…75 A mutation in the hotspot region of SRSF2 (codon P95) is found in approximately 1/3 of AdvSM patients 64,65 but is usually not detectable in patients with ISM or SSM. 25 It is more common in ASM-AHN 25,64,65 and precedes KIT D816V in these patients. 25 The frequency of SF3B1 mutations in AdvSM is low, ranging from 0 to 5%.…”

“…[61][62][63][64][65] Mutations in TET2, also detected in healthy individuals, 66 cause loss of function (i.e. regulating gene expression at the cellular level), 67 and are associated with increased self-renewal capacity of hematopoietic stem cells.…”