Tandem Double Inversion Resolves the Structural Paradox Underlying Recurrent KAT6A::NCOA2 Fusion in Acute Myeloid Leukemia.

The KAT6A::NCOA2 (formerly MOZ::TIF2) fusion is an extremely rare recurrent genetic abnormality in acute myeloid leukemia (AML), with only nine cases reported to date. It has consistently been associated with inv(8)(p11q13). However, the genomic mechanism underlying this fusion has remained unresolved. Because both KAT6A and NCOA2 are transcribed in the same reverse orientation on chromosome 8, a simple inversion is structurally insufficient to generate a transcriptionally competent fusion transcript, creating a long-standing cytogenetic paradox. We analyzed an AML case harboring a KAT6A::NCOA2 fusion using targeted genomic profiling and breakpoint-level validation. In addition to the canonical KAT6A::NCOA2 fusion, sequencing identified an unexpected MTFR1::KAT6A rearrangement. Since MTFR1 is located between KAT6A and NCOA2 on chromosome 8, we hypothesized a complex intrachromosomal rearrangement. Genomic breakpoint analysis revealed that the fusion was generated not by a single inv(8), but by two adjacent intrachromosomal inversions forming a tandem double inversion. This rearrangement reoriented genomic segments to place KAT6A and NCOA2 in a transcriptionally compatible configuration, enabling fusion formation. These findings resolve the structural paradox of KAT6A::NCOA2-positive AML by demonstrating that a cytogenetically apparent inv(8)(p11q13) can conceal a tandem double-inversion architecture that reorients KAT6A and NCOA2 into a transcriptionally compatible configuration.