TET2 loss-of-function mutations are recurrent events in a wide range of hematological malignancies and a physiologic occurrence in blood cells of healthy older adults. It is currently unknown what determines if a person harboring a somatic TET2 mutation will progress to myelodysplastic syndrome or acute myeloid leukemia. Here we develop a zebrafish tet2 mutant through which we show that tet2 loss leads to restricted hematopoietic differentiation combined with a modest upregulation of p53, which is also characteristic of many inherited bone marrow failure syndromes. Uniquely in the context of emergency hematopoiesis by external stimuli, such as infection or cytokine stimulation, lack of tet2 leads hematopoietic stem cells to undergo excessive proliferation, resulting in an accumulation of immature cells, which are poised to become leukemogenic following additional genetic/epigenetic perturbations. This same phenomenon observed in zebrafish extends to human hematopoietic stem cells, identifying TET2 as a critical relay switch in the context of stress hematopoiesis.

TET2功能丧失突变是多种血液恶性肿瘤中的反复事件，也是健康老年人血细胞中的一种生理现象。目前尚不清楚是什么决定了携带体细胞 TET2突变的人是否会发展为骨髓增生异常综合征或急性髓性白血病。在这里，我们开发了斑马鱼tet2突变体，通过它我们显示tet2缺失导致造血分化受限，同时 p53 适度上调，这也是许多遗传性骨髓衰竭综合征的特征。在外部刺激（如感染或细胞因子刺激）的紧急造血背景下，缺乏tet2导致造血干细胞过度增殖，导致未成熟细胞的积累，这些细胞在额外的遗传/表观遗传扰动后准备成为白血病细胞。在斑马鱼中观察到的同样现象延伸到人类造血干细胞，将 TET2 确定为应激造血背景下的关键继电器开关。