IGH::IL3-Rearranged B-Cell Precursor Acute Lymphoblastic Leukemia With Hypereosinophilia in a Child With a Novel PAX5 Germline Variant

Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the t(5;14)(q31;q32) chromosomal translocation resulting in an IGH::IL3 fusion is an exceptionally rare lymphoid malignancy presenting with hypereosinophilia. Germline PAX5 alterations, including sequence variants and deletions, are associated with a selective susceptibility to BCP-ALL and lymphomas, based on a limited number of affected families worldwide. Here, we report a 6-year-old male with BCP-ALL with the t(5;14)(q31;q32) translocation and harboring a novel constitutional PAX5 variant (NM_016734.3:c.[295dup];[=], p.[(Ile99Asnfs*3)];[(=)]). Despite the low representation of the leukemic clone in the bone marrow, the IGH::IL3 fusion was identified by both fluorescent in situ hybridization (FISH) and optical genome mapping (OGM). Although hypereosinophilia poses a risk of multiorgan damage, our patient exhibited only pneumonia and asymptomatic neuroimaging alterations in the central nervous system. The patient achieved remission by the end of induction and is currently continuing maintenance therapy. In line with existing literature, familial segregation of the PAX5 variant demonstrated high but incomplete penetrance, as two leukemia-free mutation carriers displayed only subclinical B lymphocyte maturation abnormalities without hypogammaglobulinemia. Our report underscores the diagnostic utility of OGM, which unequivocally demonstrated the characteristic translocation. Typically, BCP-ALL in affected family members exhibits secondary somatic aberrations involving the wild-type PAX5 allele, including structural variants or loss of heterozygosity (LOH) of chromosome 9p, as well as PAX5 somatic mutations. To our knowledge, this is the first human report aligning with animal models, which suggests that secondary alterations activating the JAK–STAT pathway may potentially contribute to leukemogenesis in a PAX5 mutation background.