PPM1D编码的磷酸酶在癌症中反复激活，尤其在与治疗相关的髓系肿瘤中尤为明显。然而，PPM1D在造血过程中的功能及其对肿瘤细胞生长的贡献尚未完全理解。我们利用条件性小鼠模型揭示了Ppm1d在造血过程中的核心作用，并验证了其作为治疗靶点的潜力。我们发现，Ppm1d调控着造血干细胞（HSCs）在存在和不存在外源性基因毒性应激情况下的竞争优势和自我更新。我们还表明，尽管Ppm1d的激活能够为细胞提供对细胞毒性治疗的抗性，但较p53缺失的程度较小，这进一步解释了人类研究中常见的克隆竞争表型。值得注意的是，即使没有Ppm1d突变，Ppm1d的丧失也会增加对白血病的体外和体内细胞毒性治疗的敏感性。对PPM1D抑制剂的易感性观察到在许多癌症类型中存在，并且依赖于p53活性。重要的是，成年小鼠中全身性失去Ppm1d的情况是可耐受的，从而支持通过药物靶向PPM1D的可耐受性。我们的数据将PPM1D增功能突变与HSCs的克隆扩张联系起来，为人类遗传观察提供了重要线索，并支持将PPM1D作为治疗靶点来治疗癌症。Copyright © 2023 American Society of Hematology.

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that while Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.Copyright © 2023 American Society of Hematology.