Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.
Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
Blood. 2024 Oct 24;144(17):1765-1780. doi: 10.1182/blood.2024024607.
The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy.
基因组学时代促进了新基因的发现，这些基因使个体易患骨髓衰竭（BMF）和血液恶性肿瘤（HM）。我们报告了 ETS 相关基因（ERG）的发现，这是一种新的常染色体显性 BMF/HM 易感性基因。ERG 是一种高度受约束的转录因子，对于确定的造血、干细胞功能和血小板维持至关重要。ERG 与其他转录因子（包括 RUNX 家族转录因子 1（RUNX1）和 GATA 结合蛋白 2（GATA2））在协调造血的基因的启动子或增强子上共定位。我们在来自 1 个家族的 3 名血小板减少症个体中发现了罕见的杂合 ERG 错义变体，在 14 名无关的 BMF/HM 个体中发现了 14 种其他 ERG 变体，包括 2 例新生病例和 3 种截断变体。与致病性种系 ERG 变体相关的表型包括血细胞减少症（血小板减少症、中性粒细胞减少症和全血细胞减少症）和 HM（急性髓细胞白血病、骨髓增生异常综合征和急性淋巴细胞白血病），发病年龄在 40 岁之前。对 20 种 ERG 变体（19 种错义变体和 1 种截断变体），包括 3 种错义人群变体，进行了功能特征分析。13 种潜在致病性红系转化特异（ETS）结构域错义变体显示出失活功能（LOF）特征，从而破坏了转录反式激活、DNA 结合和/或核定位。在小鼠胎肝细胞中过表达的选定变体未能在培养中驱动骨髓分化和细胞因子非依赖性生长，并且在移植到小鼠中时未能促进急性红白血病，这与这些变体是 LOF 变体一致。4 名个体通过同源性缺失杂合性的拷贝中性丢失显示出体细胞遗传拯救。易感性种系 ERG 变体的鉴定对患者和家族的诊断、咨询、监测和治疗策略具有临床意义，包括骨髓供者的选择以及细胞或基因治疗。
