Somatic rearrangements resulting in genomic structural variation drive malignant phenotypes by altering the expression or function of cancer genes. Pan-cancer studies have revealed that structural variants (SVs) are t...
Somatic rearrangements resulting in genomic structural variation drive malignant phenotypes by altering the expression or function of cancer genes. Pan-cancer studies have revealed that structural variants (SVs) are the predominant class of driver mutation in most cancer types, but because they are difficult to discover, they remain understudied when compared with point mutations. This review provides an overview of the current knowledge of somatic SVs, discussing their primary roles, prevalence in different contexts, and mutational mechanisms. SVs arise throughout the life history of cancer, and 55% of driver mutations uncovered by the Pan-Cancer Analysis of Whole Genomes project represent SVs. Leveraging the convergence of cell biology and genomics, we propose a mechanistic classification of somatic SVs, from simple to highly complex DNA rearrangement classes. The actions of DNA repair and DNA replication processes together with mitotic errors result in a rich spectrum of SV formation processes, with cascading effects mediating extensive structural diversity after an initiating DNA lesion has formed. Thanks to new sequencing technologies, including the sequencing of single-cell genomes, open questions about the molecular triggers and the biomolecules involved in SV formation as well as their mutational rates can now be addressed.
T-ALL is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome (PMID: 33925883). While muta...
T-ALL is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome (PMID: 33925883). While mutations, changes in gene expression and epigenetic dysregulations have been documented (PMID: 26294725; 27655895; 35585141; 23023710; 27623214), a unifying mechanism explaining the development of relapse remains unknown. To comprehensively investigate the heterogeneity of T-ALL and gain a better understanding of mechanisms driving T-ALL relapse, we conducted single-cell full-length RNA sequencing utilizing VASA-seq (PMID: 35760914). This analysis included 13 matched pediatric T-ALL patient-derived xenografts (PDX) samples obtained at initial diagnosis and relapse, generating the to date most comprehensive longitudinal single cell study in paired T-ALL samples, along with 5 non-relapsing PDX samples collected at initial diagnosis. Our dataset encompasses 11 TAL1- 3 TLX1/2-, 2 NKX2- and 2 HOXA-driven T-ALLs patients. While the predominant cell populations in these patients exhibit substantial interpatient heterogeneity, our data unveil a previously elusive subpopulation of T-ALL cells that converges at a gene-regulatory network shared between the majority of patients. This subpopulation is characterized by a molecular stem-like cell phenotype including immaturity in differentiation, persistence in the G1 cell cycling phase, metabolic quiescence and increased cell adhesion. Among the upregulated genes, we identified several surface markers previously recognized for their role in T-ALL relapse (PMID: 21487112; 20231613) or in stem-like cell maintenance in a murine T-ALL model (PMID: 29781813; 38553571), such as CD44, CD226, CD52, CD97, CD27 and ITGB7. We further identified significant enrichment of the anti-apoptotic proteins BCL-6, BCL-2 and MCL1. By contrast, NOTCH1 is among the downregulated genes in the stem-like cell population when compared to the other
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