Unknown,Transcriptomics,Genomics,Proteomics

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Re-replication generates whole-chromosomal instability and anueploidy

ABSTRACT: Aneuploidy, a hallmark of cancer, often arises from whole chromosome instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that re-replication of centromeric DNA, caused by deregulation of replication initiation proteins, efficiently induces chromosome instability––either by causing missegregation of both sister chromatids to one daughter cell or by triggering formation of an extra chromatid through a pathway dependent on homologous recombination. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of W-CIN and aneuploidy that may be relevant to cancer. Diploid strains containing a re-replicating locus were induced to re-replicate through a centromere. This compilation includes the analysis of the re-replication, as well as the copy-number determination of alleged aneuploid colonies from various backgrounds. Series contains a total of 194 copy number hybridizations and 8 re-replication profile hybridizations. Note that the VALUE field reported for all of the sample tables in this series are the log2 of the normalized Cy3/Cy5 ratio. To convert these into usable copy number profiles raise 2 to the indicated VALUE.

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Stacey Hanlon

PROVIDER: E-GEOD-55641 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Chromosomal instability (CIN), defined as an increased occurrence of chromosome segregation errors during cell division, is a prominent form of genomic instability (Bakhoum and Avi Landau, 2017). It is the major cause of aneuploidy, an imbalanced complement of whole chromosomes or chromosome arms, which is the most prevalent genetic alteration in human cancers (Vasudevan et al., 2021; Santaguida and Amon, 2015). Importantly, aneuploidy is commonly associated with ongoing CIN through consecutive cell divisions (Shelzer et al. 2011; Passerini et al., 2016), resulting in intratumor genetic heterogeneity, a central driver of cancer evolution and therapeutic resistance (Sansregret et al., 2018; Ben-David and Amon, 2019). Indeed, aneuploidy has been shown to act both as a tumor suppressor and as a tumor initiator (Weaver et al., 2007; Silk et al., 2013; Vasudevan et al., 2020), most likely depending on the specific chromosomes that are gained or lost (Ben-David et al., 2011; Sack et al., 2018; Adell et al., 2023). Despite the ubiquitous presence of CIN in several aneuploid cancer types and its clinical relevance, its presence in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored owing to the impaired proliferation of leukemic cells in vitro and the lack of reliable experimental models to comprehensively assess chromosome segregation in vivo. B-ALL is the most frequent childhood cancer, with 75% of cases occurring in children under 6 years of age, and it is characterized by the accumulation of highly proliferative immature B-cell precursors in the bone marrow (BM) (Hunger and Mullighan, 2015). The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples, but there is controversy over its presence due to the different techniques used to assess karyotype variability (Raimondi et al., 1996; Talamo et al., 2010; Alpar et al., 2014; Heerema et al.; 2007; Ramos-Muntada et al., 2022). Here, we explored the presence and the levels of CIN in different clinically-relevant aneuploid subtypes of cB-ALL using single-cell whole-genome sequencing (WGS) of primary samples to reliably assess chr-CNH, and by generating a large cohort of PDX models from primary cB-ALL samples (cB-ALL-PDX). Our results in cB-ALL-PDX models revealed variable levels of CIN in aneuploid cB-ALL subtypes, which significantly correlate with intraclonal karyotype heterogeneity and with disease progression. Additionally, mass-spectrometry analyses of cB-ALL-PDX samples revealed a CIN “signature” enriched in mitosis and chromosome segregation regulatory pathways. We speculate that this signature identifies adaptive mechanisms to ongoing CIN in aneuploid cB-ALL cells, which displayed a transcriptional signature characterized by an impaired mitotic spindle as observed by RNA-sequencing (RNA-Seq) analyses of a large cohort of primary cB-ALL patient samples. Our work might help to improve stratification of patients with cB-ALL with different levels of CIN who could benefit in the future from new therapeutic approaches aiming to target ongoing CIN.

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Re-replication generates whole-chromosomal instability and anueploidy

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