Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated preleukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation frequently found in patients with CH and leukemia. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single-cell transcriptomic profiling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population. The gene signature characteristic of this inflammatory population is associated with poor prognosis in patients with AML. Our study illustrates an example of collaboration between a genetic lesion found in CH and inflammation, leading to transformation and the establishment of blood neoplasms. Significance: Progression from a preleukemic state to transformation, in the presence of TET2 mutations, is coupled with the emergence of inflammation and a novel population of inflammatory monocytes. Genes characteristic of this inflammatory population are associated with the worst prognosis in patients with AML. These studies connect inflammation to progression to leukemia. See related commentary by Pietras and DeGregori, p. 2234 . This article is highlighted in the In This Issue feature, p. 2221

中文翻译：

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骨髓转化过程中炎症诱导的肿瘤可塑性的影响


克隆造血（CH）是一种与衰老相关的疾病，其特征是突变的白血病前期细胞的克隆生长。慢性肝炎患者患造血系统恶性肿瘤的风险增加。在这里，我们描述了一种携带复发性 TET2 错义突变的新型动物模型，这种突变常见于 CH 和白血病患者。与 CH 类似，动物在晚年出现多种髓系肿瘤，包括急性髓系白血病 (AML) 时，会表现出疾病迹象。通过对骨髓的单细胞转录组分析，我们发现老年动物的疾病进展与炎症反应的增强和异常炎症单核细胞群的出现相关。该炎症群体的基因特征与 AML 患者的不良预后相关。我们的研究展示了 CH 中发现的遗传病变与炎症之间相互作用的一个例子，导致转化和血液肿瘤的形成。意义：在 TET2 突变存在的情况下，从白血病前期状态进展到转化伴随着炎症和新的炎症单核细胞群的出现。该炎症群体的基因特征与 AML 患者最差的预后相关。这些研究将炎症与白血病的进展联系起来。参见 Pietras 和 DeGregori 的相关评论，第 17 页。第2234章本文在本期专题第 12 页中重点介绍。 2221