复杂核型（CK-AML）的急性髓系白血病与不良预后有关，而这部分仅能部分解释为潜在的TP53突变所致。尤其是在存在复杂染色体重排（如染色体结块）的情况下，CK-AML的预后非常不好。然而，基因组重排的复杂性程度对CK-AML的白血病致病表型和治疗抵抗性的贡献仍然大部分未知。我们在一个定义明确的CK-AML队列中应用一种综合分析工作流来检测结构变异（SV），该工作流基于牛津纳米孔（ONT）基因组DNA长读测序（gDNA-LRS）和高通量染色体确认捕获（Hi-C）技术。我们确定了具有极高SV密度的区域。这些重排在很大程度上由靠近哺乳动物广泛间隔重复（MIR）元素的局限性扩增组成，这些扩增通常会导致致癌融合转录本（如USP7::MVD）或致癌驱动基因的失调，这些结果通过RNA-seq和ONT直接cDNA测序得到了确认。我们将这一新现象命名为染色质大灾变。因此，我们综合运用gDNA-LRS和Hi-C的SV检测工作流能够以非常高的分辨率解析那些通过传统测序技术很难分析的区域中的复杂基因组重排，从而提供了一个重要工具来确定复杂核型癌症患者中的新致病驱动因子。版权 © 2023年美国血液学会。

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 (MIR) 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 cDNA 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.Copyright © 2023 American Society of Hematology.