Abstract
Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×103/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to routine practice in the clinic. We hypothesized that the clonality would exist in a subset of IHE/IHES patients. We aimed to investigate the candidate mutations and T-cell clonality in IHE/IHES and to explore the role of mutations in eosinophil proliferation. We performed targeted capture sequencing for 88 genes using next-generation sequencing, T-cell receptor (TCR) gene rearrangement assays, and pathway network analysis in relation to eosinophil proliferation. By targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least one candidate mutation. The most frequently affected genes were NOTCH1 (26.7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 and WT1) are functionally linked to the eosinophilopoietic pathway. Among the 21 candidate genes, five genes (MAPK1, RUNX1, GATA2, NOTCH1 and TP53) with the highest number of linkages were considered major genes. A TCR assay revealed that four patients (13.3%) had a clonal TCR rearrangement. NOTCH1 was the most frequently mutated gene and was shown to be a common node for eosinophilopoiesis in our network analysis, while the possibility of hidden T cell malignancy was indwelling in the presence of NOTCH1 mutation, though not revealed by aberrant T cell study. Collectively, these results provide new evidence that mutations affecting eosinophilopoiesis underlie a subset of IHE/IHES, and the candidate genes are inferred to act their potential roles in the eosinophilopoietic pathway.
Highlights
Idiopathic hypereosinophilia (IHE) is defined by persistent elevated eosinophils exceeding 1.5×103/μL, satisfying an absence of causal underlying diseases
Diagnosis is based on the exclusion of reactive causes or clonal causes for eosinophilia
A total of 140 candidate mutations in 59 genes were identified in 53.3% (n = 16) of the IHE/ idiopathic hypereosinophilic syndrome (IHES) patients; a median of one mutation [interquartile range (IQR), 0–3] per patient was confirmed (S3 Table)
Summary
Idiopathic hypereosinophilia (IHE) is defined by persistent elevated eosinophils exceeding 1.5×103/μL, satisfying an absence of causal underlying diseases. Diagnosis is based on the exclusion of reactive causes (i.e., parasitic infection; drug reaction; allergy and collagen vascular disorders) or clonal causes (i.e., chronic eosinophilic leukemia, not otherwise specified; myeloid-lymphoid neoplasms with eosinophilia associated with rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 [1,2,3,4] and lymphocyte-variant hypereosinophilia) for eosinophilia. The current diagnostic criteria recommend the exclusion of lymphocyte-variant hypereosinophilia either by T-cell receptor (TCR) analysis or immunophenotyping [5], but consensus has not been formed [6]. Approaches such as immunophenotyping or molecular TCR gene rearrangement studies are not often applied in routine practice, implying that a subset of IHE/IHES patients might have an underlying clonal state. The biological role of the mutations in eosinophil proliferation remains to be determined
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