Abegunde Samuel O, Buckstein Rena, Wells Richard A, Rauh Michael J
Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
Division of Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Exp Hematol. 2018 Mar;59:60-65. doi: 10.1016/j.exphem.2017.11.002. Epub 2017 Nov 28.
Clonal hematopoiesis of aging and indeterminate potential (ARCH or CHIP), driven mainly by mutations in DNMT3A and TET2, is an emerging public health issue, affecting at least 10-15% of adults older than 65 years. CHIP is associated with increased risks of de novo and therapy-related hematological neoplasms and serves as a reservoir for leukemic relapse. CHIP is also associated with increased all-cause mortality and risk of cardio-metabolic disease. The latter association may be explained, at least in part, by the effects of inactivating mutations in TET2 on progeny macrophages. We and others have shown recently that TET2-deficient macrophages are hyperinflammatory and this may exacerbate processes such as atherosclerosis. We postulated an inflammatory state associated with TET2 inactivation and/or unhealthy aging may also favor TET2-mutant hematopoietic stem and progenitor cell (HSPC) expansion. Herein, we demonstrate a clonogenic advantage for Tet2-knockout murine and TET2-mutant human HSPCs in an in vitro environment that contains the proinflammatory cytokine tumor necrosis factor-alpha (TNFα). This phenotype emerges on chronic TNFα exposure and is associated with myeloid skewing and resistance to apoptosis. To our knowledge, this is the first evidence to suggest that TET2 mutations promote clonal dominance with aging by conferring TNFα resistance to sensitive bone marrow progenitors while also propagating such an inflammatory environment. Normalizing the immune environment may present a novel strategy to control or eradicate mutant CHIP clones.
主要由DNMT3A和TET2突变驱动的衰老相关且具有不确定潜能的克隆性造血（ARCH或CHIP）是一个新出现的公共卫生问题，影响至少10% - 15%的65岁以上成年人。CHIP与原发性和治疗相关血液肿瘤的风险增加相关，并作为白血病复发的一个来源。CHIP还与全因死亡率增加和心血管代谢疾病风险相关。后一种关联至少部分可以通过TET2失活突变对后代巨噬细胞的影响来解释。我们和其他人最近表明，TET2缺陷的巨噬细胞具有高炎症性，这可能会加剧动脉粥样硬化等过程。我们推测，与TET2失活和/或不健康衰老相关的炎症状态也可能有利于TET2突变的造血干细胞和祖细胞（HSPC）的扩增。在此，我们证明了在含有促炎细胞因子肿瘤坏死因子-α（TNFα）的体外环境中，Tet2基因敲除小鼠和TET2突变人类HSPC具有克隆优势。这种表型在慢性TNFα暴露时出现，并与髓系偏斜和抗凋亡相关。据我们所知，这是第一个证据表明TET2突变通过赋予敏感骨髓祖细胞TNFα抗性，同时也传播这种炎症环境，从而促进衰老过程中的克隆优势。使免疫环境正常化可能是控制或根除突变CHIP克隆的一种新策略。
