Long-read profiling of structural variants reveals mechanisms of chemo-resistance and prognostic heterogeneity in acute lymphoblastic leukemia

作者：MA Xiao-fang, Minghao Jiang, Jin Wang, Jian‐Qing Mi, Jason W.H. Wong, Duohui Jing · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-1585 · 被引用次数：1 · 研究领域：Acute Lymphoblastic Leukemia research、Acute Myeloid Leukemia Research、Genomics and Rare Diseases

Abstract Background Acute lymphoblastic leukemia (ALL) is the most prevalent malignant tumor among children and adolescents, with poor prognosis in adults, as evidenced by a complete remission rate of <40%. Chemoresistance remains a major challenge in ALL treatments, with survival rates for resistant patients falling below 30%. While molecular subtyping based on next generation sequencing (NGS) is a key prognostic indicator of B-cell precursor ALL (BCP-ALL), chemotherapy responses often do not align with expectations based on molecular classification. This discrepancy arises, in part, because certain cases of ALL are driven by structural variants (SVs), which NGS, with its short-read sequencing approach, struggles to detect particularly large insertions, deletions, and complex rearrangements. In this study, we performed long-read sequencing (third-generation sequencing) to identify functional SVs that were missed by NGS, aiming to elucidate their roles in chemo-resistance and prognostic heterogeneity within defined BCP-ALL subtypes. Methods A panel of patient-derived xenografts (PDXs) were established, representing major BCP-ALL subtypes, including MEF2D-rearranged (n=3), BCR::ABL1/-like (n=3), TCF3::PBX1 (n=2), KMT2A-rearranged (n=2), PAX5::ETV6 (n=1), TCF3::ZNF384 (n=1) and B-other (n=2). Long-read whole-genome sequencing was performed using ONT PromethION platform. SV calling was carried out using an in-house bioinformatics pipeline that integrated 5 publicly availa...