Department of Pharmacology and Therapeutics, University of FloridaCollege of Medicine, Gainesville, FL, USA.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of FloridaCollege of Medicine, Gainesville, FL, USA.
J Exp Med. 2023 Nov 6;220(11). doi: 10.1084/jem.20230011. Epub 2023 Aug 24.
Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer (CAC) with experimental CH driven by Dnmt3a+/Δ, we found higher tumor penetrance and increased tumor burden compared with controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia, and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency and rebalanced hematopoiesis. This study provides conceptually novel insights into non-tumor-cell-autonomous effects of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies.
克隆性造血 (CH) 被定义为突变造血干细胞的克隆性扩增，而没有血液系统恶性肿瘤的诊断。在包括结肠癌在内的实体瘤患者中存在 CH 与较短的生存期相关。我们假设，骨髓来源的细胞具有 DNMT3A 的杂合功能丧失突变，DNMT3A 是 CH 中最常见的遗传改变，这有助于结肠癌的发病机制。在一种结合结肠炎相关结肠癌 (CAC) 和由 Dnmt3a+/Δ 驱动的实验性 CH 的小鼠模型中，我们发现与对照组相比，肿瘤穿透率更高，肿瘤负担增加。组织病理学分析显示结肠上皮损伤、发育不良和腺癌形成加重。结肠肿瘤的转录组谱分析鉴定出与致癌作用相关的基因特征的富集，包括血管生成。血管生成抑制剂 axitinib 的治疗消除了由 Dnmt3a 单倍不足驱动的实验性 CH 对结肠肿瘤促进作用，并重新平衡了造血。这项研究为造血改变对结肠癌发生的非肿瘤细胞自主性影响提供了新概念性的见解，并确定了潜在的治疗策略。
