摘要：2024年第九届国际干细胞论坛（IFSC）聚焦于干细胞基础研究、再生医学、细胞治疗以及临床研究指南的应用，汇集了来自世界各地的专家学者，共同探讨科学发现和技术进步的最新前沿。会议期间，《血液时讯》特邀加州大学圣地亚哥健康中心（UCSD Health）Rafae

2024年第九届国际干细胞论坛（IFSC）聚焦于干细胞基础研究、再生医学、细胞治疗以及临床研究指南的应用，汇集了来自世界各地的专家学者，共同探讨科学发现和技术进步的最新前沿。会议期间，《血液时讯》特邀加州大学圣地亚哥健康中心（UCSD Health）Rafael Bejar教授分享克隆性造血领域中从生物学现象到临床挑战的探索。现将精粹整理成文，以飨读者。

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《血液时讯》：克隆性造血在临床上的重要性日益凸显。您能简要介绍一下克隆性造血的概念及其在血液系统疾病中的作用吗？

Rafael Bejar教授：克隆性造血这一概念所描绘的是一种特定的生物学现象，即造血干细胞中发生的突变，该突变赋予了这些细胞相较于正常同类细胞更为迅速地生长与增殖能力。这一突变过程甚至可能达到一个临界点，使得血液中相当大比例的血细胞均源自这一突变的克隆细胞。值得注意的是，克隆性造血本身并不直接等同于疾病状态，但它却常常预示着诸如骨髓增生异常综合征或急性白血病等疾病的潜在风险，这些疾病同样是由造血干细胞中的突变所驱动的。

Hematology Frontier：Clonal Hematopoiesis is increasingly recognized for its clinical significance. Could you briefly explain the concept of clonal hematopoiesis and its role in hematological disorders?

Professor Rafael Bejar：Absolutely. So clonal hematopoiesis describes a process in which a mutation occurs in a hematopoietic stem cell that allows that hematopoietic stem cell to grow and proliferate more than its normal counterparts. It can actually reach a substantial fraction of all the blood cells in the blood being derived from a mutant clonal cell. Now that in and of itself is not a disease, but it is often a precursor to disorders, like myelodysplastic syndromes or acute leukemia, which are also driven by the acquisition of mutations in hematopoietic stem cells

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《血液时讯》：在您的最新报告中，您提到了针对克隆性造血的治疗靶点。能否分享一下您在这方面的研究成果，以及目前治疗克隆性造血的主要策略有哪些？

Rafael Bejar教授：在治疗领域，对于克隆性造血的研究与治疗策略的开发，人们寄予了厚望，旨在预防其可能引发的一系列不良健康后果。如前所述，克隆性造血患者不仅面临血液癌症的风险，还可能罹患与炎症相关的多种疾病，如心脏病、肺病和肝病等。若我们能找到有效干预克隆性造血的机制，或许能够显著减轻这些不良健康后果。目前，我们的治疗焦点主要集中在针对特定突变的疗法上。然而，展望未来，我们期望能够探索出更为广泛的机制，以应对多种不同类型的突变细胞。此外，抗炎通路以及其他潜在的生物学通路，特别是之前提及的原癌基因T细胞白血病/淋巴瘤1A（TCL1A），在发生突变时会呈现过度表达的状态，已成为当前研究的焦点之一。对这些通路或基因实施精准调控，或许能够有效促使突变克隆的体积缩减，从而为治疗相关疾病提供新的思路。

Hematology Frontier：In your latest report, you mentioned therapeutic targets for clonal hematopoiesis. Could you share your findings in this area, and what are the main strategies currently available for treating clonal hematopoiesis?

Professor Rafael Bejar：Yes, there's a strong interest in treating clonal hematopoiesis to prevent some of its negative health consequences. I mentioned that individuals with clonal hematopoiesis can go on to develop blood cancers, but they also have risks of inflammatory-related conditions, such as heart disease, lung disease, liver disease, and so on.

If we have a mechanism for intervening with clonal hematopoiesis, we may be able to mitigate some of these negative health consequences. So far, we have really focused on treatments that target very specific mutations. But in the future, we would like to look at more broad mechanisms that can target multiple different kinds of mutated cells. And there's interest in targeting anti-inflammatory pathways, as well as perhaps other pathways, like a gene that I mentioned, TCL1A, that can be overexpressed when these mutations are present. That might lead to a reduction in the size of the mutant clone.

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《血液时讯》：最后，关于克隆性造血的研究，您认为目前还存在哪些挑战？在未来几年内，这一领域可能会有哪些突破性的进展？

Rafael Bejar教授：在研究克隆性造血的过程中，我们面临着诸多挑战。其中一项挑战在于，我们缺乏理想的小鼠或动物模型来模拟这些状况。因此，我们迫切需要在人类身上进行深入研究。例如，剪接因子突变在动物模型中并不能很好地模拟克隆性造血的过程，但在人类身上，这些突变却是最具风险的。另一项挑战则在于，克隆性造血患者往往认为自己并未出现需要立即治疗的异常状况。因此，我们必须致力于开发出耐受性好、副作用少的治疗方法。最后，这些临床试验的开展将是一个长期的过程，因为从克隆性造血发展到血液癌症可能需要数年时间。然而，我们的临床试验往往无法等待如此长的时间。因此，我们需要开发更为先进的技术，以便在更早的时间点使用替代终点来评估药物的有效性。尽管这项工作才刚刚开始，但我们相信，通过不懈的努力和探索，我们终将能够找到治疗克隆性造血的有效方法。

Hematology Frontier：Finally, regarding the research on clonal hematopoiesis, what challenges do you think still exist? And what breakthroughs might we expect in this field in the next few years?

Professor Rafael Bejar：There are several challenges that exist when we study clonal hematopoiesis. One of them is that we don't always have good mouse or animal models for these conditions. So we really have to study them in humans. For example, splicing factor mutations don't really replicate clonal hematopoiesis in animals very well. Yet they are the highest risk mutations when we see them in humans. The other challenge is that individuals who have clonal hematopoiesis generally feel they don't have an abnormality that would require immediate therapy. So we have to develop therapies that are going to be very well tolerated and that don't have a lot of side effects. And ultimately, these clinical trials are going to take a long time, because the transition from clonal hematopoiesis to a blood cancer can take many years. And often our clinical trials don't have that long to wait. So we will need to develop better techniques for determining how effective drugs are using earlier surrogate endpoints, but that work is just beginning.

来源：肿瘤瞭望