Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study from 2,080 children and young adults with AML registered on Children's Oncology Group (COG)-AAML0531 and AAML1031 trials. Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions:104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: two each of DDX3X and TEC, with six partners (DDX3Y, CEP164, SCN2B, TREH, NAP1L1 and XPO1) observed in single patients. Patients with MLLT10 (n=127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs. 49% in non-MLLT10 patients (N=1953, P <0.001), inferior 5 year overall-survival (OS) of 38.2% vs. 65.7% (P ≤ 0.001) and a higher relapse risk of 76% vs 38.6% (P <0.001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% (P=0.628), and an OS from study entry of 40.4% vs 27.6% (P=0.361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10- without PICALM ( X::MLLT10) (P=0.788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, while KMT2A::MLLT10 patients bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high-risk features and should be prioritized for alternative therapeutic interventions. Clinical trials #NCT00372593 NCT01371981.