Diagnostic pitfalls and molecular insights in a rare RUNX1::TACC1-positive AML with t(8;21)(p11;q22).

The transforming acidic coiled-coil containing protein 1 (TACC1) gene is a recognized oncogenic driver in solid tumors through FGFR1::TACC1 fusions, but remains extremely rare in acute myeloid leukemia (AML), with only one prior case of RUNX1::TACC1 reported. Here, we describe the second documented RUNX1::TACC1 fusion AML case, occurring in an 82-year-old male with t(8;21)(p11;q22) translocation. Comprehensive molecular characterization identified four transcript variants by RNA sequencing, including a new RUNX1(E7)::TACC1(E6) isoform and reciprocal TACC1::RUNX1 fusions. Notably, initial FISH analysis misleadingly suggested FGFR1 involvement, underscoring RNA-seq's critical role in accurate rare fusion detection. While the patient showed no response to azacitidine/venetoclax, the limited number of cases precludes definitive conclusions about treatment resistance patterns. These findings expand TACC1's oncogenic spectrum to AML and warrant further investigation to determine whether RUNX1::TACC1 represents a clinically distinct molecular subtype and to elucidate its potential therapeutic vulnerabilities.