The comprehensive landscape of TTMV::RARA fusion-driven acute myeloid leukemia: from viral integration mechanisms to clinical outcomes

Acute myeloid leukemia (AML) with TTMV::RARA fusion represents a novel subtype driven by torque teno mini virus (TTMV) integration into retinoic acid receptor alpha (RARA) locus, while current understanding of its molecular features and clinical presentation relies predominantly on isolated case observations. Here, we characterize a large and independent cohort (n=25) through integrative analysis of clinical-omics data, uncovering unique features that distinguish it from classic acute promyelocytic leukemia (APL) and other AML subtypes. Our findings reveal that TTMV integrates exclusively within intron 2 of the RARA gene via microhomology-mediated end joining (MMEJ), forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72%