Senagolage Madhavi D, Blaylock Hunter Z, Khan Saira, Skuli Sarah J, Carroll Martin P, McNerney Megan E
Department of Pathology, The University of Chicago, Chicago, IL.
Committee on Cancer Biology, The University of Chicago, Chicago, IL.
Blood Neoplasia. 2025 May 19;2(3):100119. doi: 10.1016/j.bneo.2025.100119. eCollection 2025 Aug.
Monosomy 7 (-7) and deletions of chromosome arm 7q (del(7q)) are prevalent high-risk cytogenetic abnormalities that often co-occur with del(17p) (harboring ). To identify novel targeted therapies based on specific vulnerabilities in high-risk myeloid malignancies, we investigated druggable, chromosome 7-encoded essential genes that are monoallelically deleted in the context of -7/del(7q), that is, collateral lethal genes. By mining genome-wide CRISPR-Cas9 screen data sets, we identified nicotinamide phosphoribosyltransferase () on 7q22.3 as a specific susceptibility in 81.5% of -7/del(7q) malignancies. Human acute myeloid leukemia (AML) cell lines with partial loss of and primary samples from patients with -7 AML demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples. Notably, NAMPT inhibitors were equally effective in -deficient samples with loss. Furthermore, combining NAMPT and poly (ADP-ribose) polymerase (PARP) inhibitors, which augment DNA damage, resulted in synergistic therapeutic effects in -deficient AML cells. These findings indicate that heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend levels as a biomarker for NAMPT inhibitor sensitivity. This study also establishes a data-driven framework for identifying collateral lethal genes in cancers with recurrent chromosomal deletions.
单体7（-7）和染色体臂7q缺失（del(7q)）是常见的高风险细胞遗传学异常，常与17p缺失（包含……）同时出现。为了基于高风险髓系恶性肿瘤的特定脆弱性确定新的靶向治疗方法，我们研究了在-7/del(7q)背景下单等位基因缺失的、7号染色体编码的可药物靶向的必需基因，即旁系致死基因。通过挖掘全基因组CRISPR-Cas9筛选数据集，我们确定位于7q22.3的烟酰胺磷酸核糖转移酶（NAMPT）是81.5%的-7/del(7q)恶性肿瘤中的一种特定易感性因素。与对照样本相比，NAMPT部分缺失的人类急性髓系白血病（AML）细胞系以及-7 AML患者的原代样本对NAMPT抑制剂KPT-9274表现出更高的敏感性。值得注意的是，NAMPT抑制剂在NAMPT缺失且伴有TP53缺失的样本中同样有效。此外，将NAMPT抑制剂与增强DNA损伤的聚（ADP-核糖）聚合酶（PARP）抑制剂联合使用，在NAMPT缺失的AML细胞中产生了协同治疗效果。这些发现表明，NAMPT杂合性是-7/del(7q)高风险髓系恶性肿瘤中的一种治疗脆弱性，并推荐NAMPT水平作为NAMPT抑制剂敏感性的生物标志物。本研究还建立了一个数据驱动的框架，用于识别具有复发性染色体缺失的癌症中的旁系致死基因。
