Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Blood Adv. 2023 Nov 14;7(21):6520-6531. doi: 10.1182/bloodadvances.2023010887.
Acute myeloid leukemia with complex karyotype (CK-AML) is associated with poor prognosis, which is only in part explained by underlying TP53 mutations. Especially in the presence of complex chromosomal rearrangements, such as chromothripsis, the outcome of CK-AML is dismal. However, this degree of complexity of genomic rearrangements contributes to the leukemogenic phenotype and treatment resistance of CK-AML remains largely unknown. Applying an integrative workflow for the detection of structural variants (SVs) based on Oxford Nanopore (ONT) genomic DNA long-read sequencing (gDNA-LRS) and high-throughput chromosome confirmation capture (Hi-C) in a well-defined cohort of CK-AML identified regions with an extreme density of SVs. These rearrangements consisted to a large degree of focal amplifications enriched in the proximity of mammalian-wide interspersed repeat elements, which often result in oncogenic fusion transcripts, such as USP7::MVD, or the deregulation of oncogenic driver genes as confirmed by RNA-seq and ONT direct complementary DNA sequencing. We termed this novel phenomenon chromocataclysm. Thus, our integrative SV detection workflow combing gDNA-LRS and Hi-C enables to unravel complex genomic rearrangements at a very high resolution in regions hard to analyze by conventional sequencing technology, thereby providing an important tool to identify novel important drivers underlying cancer with complex karyotypic changes.
伴复杂核型的急性髓系白血病（CK-AML）预后较差，这在一定程度上可以用潜在的 TP53 突变来解释。尤其是在存在复杂的染色体重排，如染色体重排的情况下，CK-AML 的预后极差。然而，这种程度的基因组重排复杂性促成了 CK-AML 的白血病发生表型，而 CK-AML 的治疗耐药性在很大程度上仍不清楚。在一个明确定义的 CK-AML 队列中，应用基于牛津纳米孔（ONT）基因组 DNA 长读测序（gDNA-LRS）和高通量染色体确认捕获（Hi-C）的结构变异（SV）检测的综合工作流程，确定了 SV 密度极高的区域。这些重排在很大程度上由富含哺乳动物广泛散布的重复元件附近的局灶性扩增组成，这些元件通常导致致癌融合转录本，如 USP7::MVD，或通过 RNA-seq 和 ONT 直接互补 DNA 测序证实的致癌驱动基因的失调。我们将这种新现象称为染色体重排剧变。因此，我们的综合 SV 检测工作流程结合 gDNA-LRS 和 Hi-C，可以在传统测序技术难以分析的区域以非常高的分辨率揭示复杂的基因组重排，从而为识别具有复杂核型变化的癌症的新重要驱动因素提供了重要工具。
