Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell transformation, we generated asxl1 haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of asxl1 leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of bim and bid Half of the asxl1^{+/ -} zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of asxl1 combined with heterozygous loss of tet2 led to a more penetrant MPN phenotype, while heterozygous loss of asxl1 combined with complete loss of tet2 led to acute myeloid leukemia (AML). These findings support the use of asxl1^{+/ -} zebrafish as a strategy to identify small-molecule drugs to suppress the growth of asxl1 mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of ASXL1.

中文翻译：

---

asxl1的破坏导致斑马鱼的骨髓增生性肿瘤。

额外的性梳样转录调节因子1（ASXL1）基因的体细胞功能丧失突变是人类骨髓恶性肿瘤中常见的遗传异常，并诱导突变的造血干细胞（HSC）的克隆扩增。为了了解ASXL1破坏如何导致骨髓细胞转化，我们使用基因组编辑技术生成了asxl1单倍体不足和无效的斑马鱼品系。在这里，我们显示asxl1的纯合丢失导致新形成的HSCs凋亡。凋亡通过bim和bid上调介导的线粒体凋亡途径发生。asxl1的一半^{+ / -} 斑马鱼到5个月大时就有骨髓增生性肿瘤（MPN）。的杂合子丢失ASXL1与杂合子丢失组合TET2导致了更加渗透剂MPN表型，而的杂损失ASXL1与完全丧失组合TET2导致急性髓性白血病（AML）。这些发现支持使用ASXL1 ^{+ / -}斑马鱼作为一项战略，以确定小分子药物来抑制生长ASXL1在与体细胞获得性突变失活突变的个体而不是野生型的造血干细胞ASXL1。