The comprehensive landscape of TTMV::RARA fusiondriven 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 the retinoic acid receptor α (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, forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72%, age <18 years) and often presented with extramedullary diseases (24% with myeloid sarcoma, 16% with central nervous system infiltration). Blasts displayed APL-like morphology and immunophenotype but lacked PML::RARA, instead harboring TTMV::RARA with recurrent i(17)(q10) abnormalities (24%). Unsupervised clustering revealed it as a molecularly distinct subgroup. Transcriptomic profiling identified a Wnt-activated/extracellular matrix-dysregulated signature, driving leukemogenesis via dual mechanisms of clonal expansion and metastatic pathways. Despite achieving a 96% complete remission rate with induction therapy, long-term outcomes were significantly inferior, with 2-year event-free survival and relapse-free survival rates of 53.6% and 53.8%, respectively. Hematopoietic stem cell transplantation achieved durable remission in nine of 11 patients, particularly those with extramedullary disease or i(17)(q10) abnormalities. Conclusively, this work establishes TTMV::RARA as a novel AML subtype, highlighting the need for viral screening in APL-like cases and hematopoietic stem cell transplantation prioritization for this subset.