Genetic Diversity in KMT2A-r and KMT2A-Wt Groups: Assessing the Prognostic Value of Markers in BCP-ALL Among Infants

Background/Objectives

Infant BCP-ALL is classified into KMT2A-r and KMT2A-wt groups, both showing heterogeneity. KMT2A rearrangements indicate poor prognosis, but outcomes vary by fusion partner. The KMT2A-wt group includes cases in the B-other ALL subgroup, with unclear prognostic significance. We aim to improve understanding of molecular subtypes in KMT2A-r and KMT2A-wt, focusing on NUTM1 and PAX5 rearrangements.

Methods

We analyzed 175 infants (aged 0–365 days) diagnosed with BCP-ALL from 2010 to 2023 at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Genomic aberrations were identified by karyotyping, FISH and RNA-seq. RNA-seq was performed using the Illumina, and gene fusions were validated by Sanger sequencing.

Results

There was no difference in survival based on KMT2A partner genes. The KMT2A::AFF1 group showed similar outcomes to other partners, with 2-year EFS of 36% (95% CI, 21%–59%) versus 37% (95% CI, 23%–60%) (log-rank test, p = 0.9). In the KMT2A-wt group (n = 33, 17.7% of cases), NUTM1-r (n = 9) and PAX5-r (n = 10) accounted for 27% and 30.3%, respectively. The NUTM1-r and PAX5-r groups showed excellent survival rates, with 2-year EFS of 80% (95% CI, 52%–100%) and 100% (95% CI, 100%–100%), respectively, but the small cohort size limit the statistical power of the analysis (log-rank test, p = 0.9).

Conclusions

Survival in the KMT2A-r group did not differ by fusion partner. NUTM1 rearrangements showed a favorable prognosis, and PAX5-rearranged patients had better outcomes than previously reported. In the NUTM1-r group, the most common fusion, BRD9:NUTM1, showed variability in breakpoints (Exons 3, 8, and 14 of BRD9).