Molecular genetics plays a pivotal role in the diagnosis of chronic eosinophilic leukemia (CEL), primarily to differentiate it from other hematologic neoplasms. Initial diagnostic steps involve screening for elevated PDGFRA expression—a marker for PDGFRA rearrangements. Furthermore, tests are conducted to detect the FIP1L1::PDGFRA fusion transcript and the ETV6::ABL1 fusion. These assessments are crucial for excluding myeloid/lymphoid neoplasms with eosinophilia and specific genetic rearrangements, a distinct entity requiring different management strategies.
The definitive diagnosis of CEL hinges on establishing clonality. Molecular genetic analyses are essential to confirm clonality, thereby distinguishing CEL from idiopathic hypereosinophilic syndrome (HES). To achieve this differentiation, investigations target specific mutations, including KIT p.D816V, JAK2 p.V617F, JAK2 exon 13 mutations, and STAT5B p.N642H. These mutations, while present in a small percentage (1% to 4%) of hypereosinophilia cases (WHO 2022), serve as clonal markers.
For a more comprehensive clonality assessment, next-generation sequencing (NGS) of a myeloid gene panel is highly recommended. Recurrent mutations in CEL have been identified in genes such as ASXL1, IDH1, IDH2, TP53, SRSF2, SH2B3, TET2, SETBP1, SF3B1, EZH2, CBL, and NF1 (Reiter & Gotlib 2017, Morsia et al. 2020). It is important to note that in elderly individuals, mutations in these genes can occur without indicating a hematologic neoplasm.
The detection of mutations in myeloid neoplasm-associated genes with a variant allele frequency of ≥2% in the absence of other signs of hematologic neoplasia or cytopenia points towards clonal hematopoiesis of undetermined potential (CHIP). CHIP is particularly relevant in the elderly and commonly involves genes like TET2, ASXL1, and DNMT3A (Steensma 2018). Therefore, careful consideration of these genes is crucial when evaluating clonality in the diagnostic process for chronic eosinophilic leukemia, as outlined by the WHO 2022 guidelines.
