在本文中，我们回顾了不确定潜能克隆造血（CHIP）与慢性骨髓增殖性肿瘤（MPN）、自身免疫性疾病（AD）和心血管疾病（CAD）之间联系的可能机制。 CHIP 的特征是外周血中存在等位基因频率 >2% 的克隆突变，但不伴有不典型增生、明显的血液肿瘤或血细胞计数异常。老年健康个体的患病率可能达到20%，被认为是骨髓增生异常肿瘤和急性白血病的危险因素。在 MPN 中，CHIP 通常与 JAK2V617F 或 DNMT3A、TET2 或 ASXL1 等突变相关，这些突变使 CAD 增加 12.1 倍和 1.7-2 倍。具体而言，JAK2 突变细胞产生过多的细胞因子和活性氧，导致骨髓微环境发生促炎性改变。因此，发生血栓的可能性受到 JAK2V617F 突变的变异等位基因频率 (VAF) 的影响，这似乎也与维持血栓形成的抗内皮细胞抗体相关。然而，DNMT3A 突变会诱导促炎性 T 细胞极化并激活炎症小体复合物，而 TET2 下调则导致内皮细胞自噬和炎症因子上调。因此，在 TET2 和 DNMT3A 相关 CHIP 患者中，炎性体过度激活是 CAD 的潜在原因。 CHIP 也发生在患有大血管和小血管炎的患者中，而 AD 更常见于 MPN。在这些疾病中，单核细胞和中性粒细胞在中性粒细胞胞外陷阱（NET）以及抗内皮细胞抗体的形成中发挥关键作用，从而产生最终的促凝血作用。 AD，例如系统性红斑狼疮、牛皮癣和关节炎，其特征还在于 Rho 相关卷曲螺旋蛋白激酶 2 (ROCK2) 的过度表达，ROCK2 是一种丝氨酸/苏氨酸激酶，可过度激活 JAK-STAT 通路。有趣的是，在骨髓恶性肿瘤中也观察到了 ROCK2 的过度激活，它促进了白血病细胞的生长和存活。总之，CHIP 的存在，无论是否伴有肿瘤，都可能与自身免疫表现和血栓形成相关。存在这些表现时，有必要考虑“疾病缓解疗法”，可以减轻克隆负担或抑制克隆激活的 JAK 通路。版权所有 © 2023 Fulvio, Baldini, Mosca, di Paolo, Bocci, Palumbo,卡乔拉、米廖里尼、卡乔拉和加林贝尔蒂。

In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7-2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a "disease-modifying therapy" that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.Copyright © 2023 Fulvio, Baldini, Mosca, di Paolo, Bocci, Palumbo, Cacciola, Migliorini, Cacciola and Galimberti.