造血干细胞（HSCs）确保有机体终身产生血细胞，并且为此需要在平稳状态以及应对压力或损伤时平衡自我更新、增殖、分化和迁移。重要的是，HSCs异常增殖导致血液恶性肿瘤，因此，包括p53在内的多种抑癌途径的严格调控是必不可少的。蛋白磷酸酶镁依赖性1δ（PPM1D）是p53的负调节因子，在诱导基因毒性应激后促进细胞存活。PPM1D最后一个外显子的截断突变导致产生稳定的酶活性蛋白，并常与克隆性造血异常相关。我们使用转基因小鼠模型证明截断的PPM1D在基础条件下降低HSCs的自我更新，但在暴露于电离辐射后促进侵袭性AML的发展。抑制PPM1D抑制了携带截断PPM1D的白血病干细胞和祖细胞的克隆生长，并显著提供了对辐射引起的细胞生长的保护。总之，我们证明截断的PPM1D影响HSC维持，破坏正常造血过程，并且其抑制在治疗诱导AML的背景下可能是有益的。©2023. 作者。

Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.© 2023. The Author(s).