PPM1D in Clonal Hematopoiesis and Malignancies

摘要 克隆性造血(CH)是指单个造血干细胞 (HSCs)对外周血产生的贡献不成比例。患有慢性丙型肝炎的患者在 与那些没有CH的人相比，患恶性血液病的风险要大得多。 最近对CH相关白血病的分析发现，在一些 癌症相关基因，包括PPM1D，它以前与白血病无关 发展。此外，还观察到PPM1D突变发生在 既往非造血固体化疗后的继发性白血病 肿瘤。PPM1D编码野生型P53诱导的磷酸酶1(Wip1)，它是 在DNA损伤过程中被P53上调，并在体内平衡地作用于去磷酸化和 下调DNA损伤反应蛋白。PPM1D突变通常是C-末端 截断导致Wip1蛋白水平急剧上升的突变。一直以来 假设PPM1D突变增强造血干/祖细胞的适合性 承受化疗压力，并可能进一步导致恶性进展 HSC来源的细胞在其他驱动因素突变的背景下。 PPM1D突变增强造血细胞适合性的确切机制 人们对此仍然知之甚少。在本申请中，我们建议使用细胞、动物和人类患者 更好地了解PPM1D突变如何推动克隆性造血和 白血病发生，长期目标是测试可能靶向的治疗方法 表现出这种突变的恶性肿瘤患者。我们提出了四个具体目标， 包括(1)长期造血与基因工程中癌症的比较 带有PPM1D生殖系截断突变的小鼠；(2)竞争性HSC移植的应用 实验分析影响Pre-Pre的进化和结果的适应度景观 白血病的造血；(3)使用基因组筛选和细胞分析来鉴定 正常人PPM1D突变的途径和功能机制 造血细胞和白血病细胞；(4)PPM1D相关突变的研究 继发性白血病和骨髓增生异常综合征细胞的特征和克隆构筑 发生于先前因原发肿瘤而接受化疗的患者。这些 对这种新发现的白血病相关癌基因的综合研究可能会指导 治疗药物的选择和阐明进化选择的机制 驱动从克隆显性向恶性进展的突变。

ABSTRACT Clonal hematopoiesis (CH) is a condition in which individual hematopoietic stem cells (HSCs) contribute disproportionately to peripheral blood production. Individuals with CH are at significantly greater risk of developing hematologic malignancies compared to those without CH. Analysis of CH-associated leukemias has recently revealed recurrent mutations in a number of cancer-associated genes, including PPM1D, which was previously not associated with leukemia development. In addition, PPM1D mutations have been observed in patients developing secondary leukemias after having received chemotherapy for prior non-hematopoietic solid tumors. PPM1D encodes the Wildtype p53-Induced Phosphatase 1 (WIP1), which is upregulated by p53 during DNA damage and acts homeostatically to dephosphorylate and downregulate DNA damage response proteins. PPM1D mutations are generally C-terminal truncating mutations that cause dramatic increases in WIP1 protein levels. It has been hypothesized that PPM1D mutations enhance fitness of hematopoietic stem and progenitor cells subjected to chemotherapeutic stress and may further contribute to malignant progression of HSC-derived cells in the context of other driver mutations. The precise mechanisms by which PPM1D mutations enhance hematopoietic cell fitness remain poorly understood. In this application we propose cellular, animal, and human patient studies to better understand how PPM1D mutations may drive clonal hematopoiesis and leukemogenesis with a long-term goal of testing therapeutic approaches that might target patients with malignancies that display such mutations. We propose four specific aims that include (1) the comparison of long term hematopoiesis and cancers in genetically engineered mice with a germline truncating mutation in Ppm1d; (2) the use of competitive HSC transplant experiments to analyze the fitness landscapes that impact the evolution and outcome of pre- leukemic hematopoiesis; (3) the use of genomic screens and cellular assays to identify pathways and elucidate functional mechanisms associated with PPM1D mutations in normal hematopoietic cells and leukemic cells; and (4) investigation of PPM1D-associated mutation signatures and clonal architecture of secondary leukemia and myelodysplastic syndrome cells arising in human patients exposed to previous chemotherapy for a primary tumor. These comprehensive studies on this newly discovered leukemia-associated oncogene may guide choice of therapeutic agents and elucidate mechanisms underlying the evolutionary selection of mutations that drive the progression from clonal dominance to malignancy.