第七号染色体的完全或部分缺失（-7/del7q）是骨髓系肿瘤（MN）中最常见的染色体异常之一，并与疾病预后不良相关。-7/del7q的疾病生物学以及造成白血病发生的基因尚未完全阐明。染色体缺失可能由于包含在删除区域中的一倍体缺陷（HI）基因而产生克隆性易感性。因此，HI基因是合成致死策略的潜在靶点。通过对600多个-7/del7q MN样本的最全面的多模态分析，我们阐明了疾病生物学，并列举了最一致删除和HI基因的列表。其中，鉴定出27个潜在的合成致死靶点基因，具有以下特点：（i）对半合子/纯合子LOF突变不敏感；（ii）在敲除小鼠中表现为胚胎致死；（iii）通过CRISPR和shRNA敲除筛选对白血病细胞具有易感性。在-7/del7q细胞中，我们还鉴定出了26个在其他染色体上映射的上调或下调的基因，作为下游通路或补偿机制。我们的发现揭示了-7/del7q MN的发病机制，而27个潜在的合成致死靶点基因和26个差异表达的基因为-7/del7q提供了治疗窗口。© 2023. 作者。

Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.© 2023. The Author(s).