Acute leukemias with chimeric fusion genes involving FET family proteins and ETS-like transcription factors often present with unique clinical and pathological characteristics, according to a June 27 mini-review. The review summarizes the clinical and pathological features of acute leukemia cases harboring rearrangements involving the fused in sarcoma (FUS) or Ewing sarcoma breakpoint region 1 (EWSR1) genes.
An extensive literature review was conducted on reported acute leukemia cases with fusions involving FUS or EWSR1. Details of these reported cases, as well as summarized information, are presented in the review.
Rare cases of acute leukemia have been found to harbor either FUS or EWSR1 gene rearrangements with ETS or non-ETS proteins as partners, demonstrating heterogeneous clinical and pathological features. Acute leukemias carrying FUS gene rearrangements present with diverse immunophenotypes and are predominantly, but not exclusively, acute myeloid leukemia (AML), with ERG as the most frequent fusion partner. In contrast, acute leukemias with EWSR1 gene rearrangements more commonly present as B-cell acute lymphoblastic leukemia (ALL) and mixed phenotypic acute leukemia (MPAL), with ZNF384 as the predominant partner.
Currently, FUS::ERG-positive AML is the only specific entity with a FET::ETS fusion that is formally recognized in both the World Health Organization 5th edition hematolymphoid tumor classification (WHO-HEM5) and International Consensus Classification systems. Cytogenetic karyotyping and fluorescence in situ hybridization remain crucial tools for detecting chromosomal translocations in over half of acute leukemias harboring FUS or EWSR1 gene rearrangements; however, some patients may exhibit a normal karyotype, requiring advanced molecular diagnostic methods. The review notes that EWSR1-rearranged leukemias can be difficult to distinguish from Ewing sarcoma and therefore require particular attention.
The authors state that as more cases are identified and additional data become available, it may be justified to expand this category of acute leukemias to include other specific entities such as those involving FUS::FLI1 and FUS::FEV fusions. However, further data are needed before making such subclassifications. They also note that AML cases with EWSR1 rearrangements are exceedingly rare and display considerable variability. Cases of B-ALL or B/myeloid MPAL featuring the EWSR1::ZNF384 fusion may be better classified together with other ZNF384-rearranged subtypes.
Advanced molecular diagnostic methods—especially RNA-based next-generation sequencing—are suggested for improving accurate diagnosis of these rare forms of leukemia. Additional pathologic workup using immunohistochemical staining is recommended to help differentiate between EWSR1-rearranged leukemia and Ewing sarcoma.
