Clonal and genomic determinants of e1a2 BCR::ABL1 chronic myeloid leukemia: A Fi-LMC study

The rarer p190 (e1a2) transcript in chronic myeloid leukemia (CML) is associated with atypical presentations; yet, its biological basis remains poorly understood. Using a cohort of 60 patients including 42 chronic phase patients age-matched 1:1 with 42 e13a2/e14a2 patients in the chronic phase, we investigated the clinical, genomic, and clonal features of e1a2 BCR::ABL1 CML. We identified 60 e1a2 BCR::ABL1 CML patients showing distinctive hematologic features including lower leukocyte and platelet counts and higher monocytosis (12.3% vs. 2.0%, P < 0.001). Additional somatic mutations were detected in 37/42 (88%) e1a2 BCR::ABL1 cases compared with 7/42 (17%) e13a2/e14a2 BCR::ABL1 cases. The mutational spectrum was dominated by ASXL1 and TET2, and closely resembled CMML-like profiles. Genomic breakpoint sequences of 34 e1a2 BCR::ABL1 cases showed that BCR and ABL1 coordinates were similar to those observed in 394 B-ALL. Longitudinal mutational tracking revealed two distinct clonal architectures. In 71% of patients, mutations disappeared with molecular response, consistent with BCR::ABL1 as the founding event. In contrast, 29% of patients had mutations with stable VAFs, while BCR::ABL1 transcript levels decreased after treatment, indicating that the fusion had been acquired within a pre-existing mutated clone. Single-cell genotyping experiments confirmed these clonal architectures. These patients frequently developed cytopenias under tyrosine kinase inhibitor therapy and half required red blood cell transfusions, reflecting persistence of the ancestral clone rather than BCR::ABL1-driven disease. These findings show that e1a2 BCR::ABL1 CML frequently arises within complex, premutated clonal backgrounds, providing a biological basis for its atypical presentation and heterogeneous treatment response.