Staring inside of Idiopathic Hypereosinophilia: Identification of Clonality Using Targeted Exome Sequencing

Idiopathic hypereosinophilia (IHE) has been a disorder of uncertain etiology, characterized by persistent elevation of blood eosinophil count exceeding 1.5x10³/μL without evidence of reactive and clonal causes. When end-organ damage due to eosinophilic infiltration is present, idiopathic hypereosinophilic syndrome (IHES) is diagnosed. As the name 'idiopathic' implies the uncertain etiology, the nature of eosinophilic proliferation is unclear whether benign or clonal. While T cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to the routine practice in clinic. We hypothesized that the clonality would exist in patients classified into IHE/IHES. The bone marrow cells of 30 IHE patients were retrospectively evaluated.The T cell receptor (TCR) assay and the targeted sequencing for 88 genes related to hematologic malignancies were performed. After being analyzed, the candidate mutations were subjected to pathway analysis.Through the targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least 1 candidate mutation. The most frequently affected genes were NOTCH (n=8); SCRIB and STAG2 (n=5); SH2B3 (n=4). Remarkably, we identified recurrent somatic mutations in 4 genes with 5 patients (16.7%); MPL^Y521X (n=2), SCRIB^E795X (n=2), ASXL1^G646f (n=3) and STAG2^E249X (n=2). A known mutation TP53^V216M was confirmed in an IHE patient. Interestingly, the TCR assay revealed that 4 of 30 patients (13.3%) had a clonal TCR rearrangement. Skin involvement was described in patients with clonal T cell population. Through the pathway analysis, the role of these genes in eosinophilia was identified. These results highly suggest that these genes are likely related to clonality of hypereosinophilia.This study revealed that somatic mutations affecting hematopoiesis and monoclonal T cell clones underlie idiopathic hypereosinophilia. It would be valuable to extend our findings on the molecular profiling of hypereosinophilia to the further study discovering the clonality of IHE.