All genetic subtypes of B-cell acute lymphoblastic leukemia exhibit increased incidence rates in children with Down syndrome

Abstract

Children with Down syndrome (DS) have a 20-fold increased risk and 2% lifetime risk of developing B-cell acute lymphoblastic leukemia (B-ALL) [1,2,3]. Despite improvements over time, survival in DS-ALL remains consistently 10 to 20% lower compared to non-DS-ALL, due to both increased relapse and more frequent and severe treatment-related toxicities [4,5,6].

Notably, the somatic genomic landscape of DS-ALL differs from that of non-DS-ALL. CRLF2 rearrangements (CRLF2-r) and JAK2 mutations are more frequent in DS-ALL, whereas most other subtypes are less frequent [4, 7,8,9,10,11]. A recent study of 295 DS-ALL cases in comparison to 2 257 non-DS-ALL cases showed that CRLF2-r was 9 times more frequent in DS-ALL (54.2% vs 6.0%), along with an increased prevalence of JAK2 mutations (26.2% vs 3.5%) [12]. This study also identified eight additional subtypes with significantly different frequencies between DS-ALL and non-DS-ALL: C/EBPalt and IGH::IGF2BP1 subtypes were highly enriched in the DS-ALL cohort, whereas high hyperdiploid, BCR::ABL1-like, BCR::ABL1, KMT2A-rearranged (KMT2A-r), DUX4-rearranged (DUX4-r), and intrachromosomal amplification of chromosome 21 (iAMP21) subtypes were underrepresented in DS-ALL compared with non-DS-ALL.