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

Abstract

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% <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 (CR) rate with induction therapy, long-term outcomes were significantly inferior, with 2-year event-free survival (EFS) and relapse-free survival (RFS) rates of 53.6% and 53.8%, respectively. Hematopoietic stem cell transplantation (HSCT) achieved durable remission in 9 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 HSCT prioritization for this subset.