Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Abstract

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a “CIN signature” enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

“…Importantly, CIN leads to ongoing chromosomal mis-segregation throughout cell progeny, resulting in tumour cell populations with different karyotypes, thus increasing intra-tumoural heterogeneity [29,30]. Notably, aneuploidy can trigger increased genomic instability (GIN) and CIN [31,32], with Passerini et al, showing that aneuploidy increases the frequency of pre-mitotic errors and DNA damage and enhanced sensitivity to replication stress, ultimately leading to genomic rearrangements. The reverse is also true as GIN induced by DNA mutations and epigenetic modifications (DNA methylation and histone modification) has been shown to lead to deletions/duplications [25,33].…”