克隆造血组织（CH）被定义为克隆扩张的突变造血干细胞，且未诊断出血液恶性肿瘤。在固体肿瘤患者中，包括结肠癌在内，存在CH与较短的生存期相关。我们假设DNMT3A的杂合性缺失功能突变来源于骨髓细胞，是结肠癌发病机制的贡献因素。使用结合Dnmt3a+/Δ驱动实验性CH的溃疡性结肠癌（CAC）小鼠模型，我们发现相较于对照组，转基因小鼠的肿瘤穿透性更高且肿瘤负担增加。组织病理学分析显示强调结肠上皮细胞损伤、异常增殖和腺癌形成。结肠肿瘤的转录组学分析发现了与癌变相关的基因特征的富集，包括血管生成。使用血管生成抑制剂axitinib治疗消除了由Dnmt3a部分缺失驱动的实验性CH对结肠肿瘤促进作用，并重新平衡了造血系统。本研究为探究造血系统改变对结肠癌发生的非肿瘤细胞自主作用提供了全新的概念性见解，并且鉴定了潜在的治疗策略。© 2023 Feng et al.

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.© 2023 Feng et al.