Bentivegna Sofia, Almosailleakh Marwa, Zhao Lin-Pierre, Schuster Mikkel Bruhn, Benquet Sébastien, Balhuizen Alexander, Munch-Petersen Helga Fibiger, Sjö Lene Dissing, Andersen Mads Hald, Dulphy Nicolas, Porse Bo, Grønbæk Kirsten
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
Exp Hematol Oncol. 2025 Jan 30;14(1):10. doi: 10.1186/s40164-025-00598-8.
Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where blood or bone marrow cells carry mutations associated with hematological malignancies. Individuals with CHIP have an increased risk of developing hematological malignancies, atherosclerotic cardiovascular disease, and all-cause mortality. Bone marrow transplantation (BMT) of cells carrying CHIP mutations into irradiated mice are useful procedures to investigate the dynamics of clonal expansion and potential therapeutic strategies, but myeloablative conditioning can induce confounding effects. We established a non-conditioned BMT model using C57BL/6J-Kit/J (W) recipient mice to overcome the unwanted effects of irradiation. Conditional Tet2 deletion using tamoxifen was used to obtain Tet2 cells from donor mice. Total BM Tet2 cells were transplanted into W recipients, and longitudinal and terminal analyses at 10 months post-BMT were performed. We showed that W mice can be used for BMT procedures without myeloablative pre-conditioning. The transplantation of Tet2 BM cells led to a progressive expansion of the donor cells in W recipients. By modulating the numbers of Tet2 cells transplanted, recipient mice developed features of clonal hematopoiesis or myeloid malignancies. In conclusion, our model is an alternative to conventional irradiation-based transplantation models to study mechanisms underlying malignant hematopoiesis without confounding effects derived from pre-conditioning regimen.
不确定潜能的克隆性造血（CHIP）是一种血液或骨髓细胞携带与血液系统恶性肿瘤相关突变的病症。患有CHIP的个体发生血液系统恶性肿瘤、动脉粥样硬化性心血管疾病和全因死亡率的风险增加。将携带CHIP突变的细胞进行骨髓移植（BMT）到受照射小鼠中是研究克隆扩增动力学和潜在治疗策略的有用方法，但清髓性预处理会产生混杂效应。我们使用C57BL/6J-Kit/J（W）受体小鼠建立了一种非预处理的BMT模型，以克服照射的不良影响。使用他莫昔芬进行条件性Tet2缺失以从供体小鼠获得Tet2细胞群。将总骨髓Tet2细胞群移植到W受体小鼠中，并在BMT后10个月进行纵向和终末分析。我们表明W小鼠可用于无需清髓性预处理的BMT程序。Tet2骨髓细胞群的移植导致W受体小鼠中供体细胞的逐渐扩增。通过调节移植的Tet2细胞群数量，受体小鼠出现了克隆性造血或髓系恶性肿瘤的特征。总之，我们的模型是传统基于照射的移植模型的替代方法，用于研究恶性造血的潜在机制，而不会受到预处理方案产生的混杂效应影响。
