Abstract B026: Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL

Abstract Infant acute lymphoblastic leukemia (ALL) is characterized by high frequency of rearrangements in KMT2A (KMT2Ar), associated with poor outcomes. Infants lacking KMT2Ar typically have superior outcomes, but remain understudied. Here, we use whole genome and transcriptome sequencing to define driver mutations and transcriptional phenotypes in non-KMT2Ar infant ALL. Based on two index cases, we initially suspected that some infants with high-risk clinical features harbored clinically undetected non-canonical alterations to the KMT2A gene; however, we find no such evidence in our data. Instead, we find that these infants acquire other clinically relevant features such as Ph-like expression signatures, fusions impacting ZNF384, TCF3, ETV6::RUNX1, PAX5 or NUTM1, and events in known tumor genes such as CDKN2A, NOTCH1, and others. By mapping transcriptional profiles between infant and childhood B-ALL, we find that - in the absence of KMT2Ar - infant ALL resembles well defined childhood B-ALL subtypes, sharing the same genetic drivers. NUTM1 fusions are particularly enriched in infants compared to older children, and are associated with decreased MHC-Class II expression and B-cell developmental signaling pathways. Ph-like transcriptional signatures were apparent in several infants and confirmed by machine learning driven classification. Overall, our data support a common developmental origin of ALL without KMT2Ar in infants and children. Citation Format: Matthew Zatzman, Jennifer Seelisch, Federico Comitani, Fabio Fuligni, Scott Davidson, Kyoko E. Yuki, Lisa-Monique Edwards, Ledia Brunga, Erin Guest, Stephen P. Hunger, Mignon L. Loh, Elizabeth A. Raetz, John Chen, Jack Bartram, Johann K. Hitzler, Patrick A. Brown, Sumit Gupta, Adam Shlien. Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B026.