An enhanced myeloid NGS panel that incorporates RNA-based fusion testing uncovered leukemia-defining rearrangements missed by standard cytogenetics in a University of Michigan review of 601 acute myeloid leukemia cases. The assay identified gene fusions in 14.8% of samples, including 23 cryptic events—about 4% of all AML cases—that would not have been detected by karyotyping alone. Hidden NUP98 and KMT2A rearrangements were most common. RNA testing also clarified borderline or incomplete cytogenetic findings in additional cases. The results support integrating RNA-based fusion detection into routine AML diagnostics to improve molecular classification and guide treatment selection.