Department of Pathology, NYU Grossman School of Medicine, New York, New York.
Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, New York.
Cancer Discov. 2022 Oct 5;12(10):2392-2413. doi: 10.1158/2159-8290.CD-21-1146.
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.
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.
克隆性造血（CH）是一种与衰老相关的病症，其特征是突变的白血病前体细胞的克隆性生长。患有 CH 的个体发生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 TET2 错义突变的新型动物模型，该突变在患有 CH 和白血病的患者中经常发现。与 CH 相似，动物在生命后期出现疾病迹象，此时它们会发展出广泛的髓性肿瘤，包括急性髓系白血病（AML）。通过对骨髓进行单细胞转录组谱分析，我们表明，老年动物的疾病进展与增强的炎症反应和异常炎症单核细胞群的出现相关。这种炎症群体的特征基因与 AML 患者的预后不良相关。我们的研究说明了在 CH 中发现的遗传病变与炎症之间的协同作用导致转化和血液肿瘤的建立的一个例子。
在 TET2 突变存在的情况下，从白血病前期状态向转化的进展与炎症的出现和新型炎症性单核细胞群的出现相关。这种炎症群体的特征基因与 AML 患者的最差预后相关。这些研究将炎症与向白血病的进展联系起来。请参阅 Pietras 和 DeGregori 的相关评论，第 2234 页。本文在本期特色栏目中重点介绍，第 2221 页。
