Always stressed but never exhausted: how stem cells in myeloid neoplasms avoid extinction in inflammatory conditions.
Always stressed but never exhausted: how stem cells in myeloid neoplasms avoid extinction in inflammatory conditions.
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DOI：
10.1182/blood.2022017152
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发表时间：
2023-06-08
期刊：
影响因子：
20.3
通讯作者：
Deininger, Michael
中科院分区：
文献类型：
--
作者：
Zhao, Helong Gary;Deininger, Michael
慢性或反复发作的急性炎症会导致正常造血干细胞(HSCs)的磨损，这可能会导致造血衰竭，但它们会推动髓系恶性肿瘤及其前体克隆性造血的进展。慢性炎症中的造血与髓系恶性肿瘤，特别是骨髓增生性肿瘤(MPN)的持续增殖之间存在着机械上的相似之处。进入休眠是一种深度静止状态，以低氧化磷酸化、低糖酵解、蛋白质合成减少和自噬增加为特征，是长期保存HSCs和可能的MPN SCs的关键。休眠的代谢特征类似于滞育，滞育是一种由不利环境条件引发的胚胎发育受阻状态。为了在炎症性MPN环境中与正常同龄人竞争，MPN SCs共同选择了HSCs避免衰竭的机制，包括负调节因子信号的衰减，与激活细胞因子信号的隔离，抗炎信号，以及表观遗传重新编程。我们认为，新的治疗策略可能源于将髓系恶性肿瘤概念化为一个失衡的生态系统，在这个生态系统中，残留的正常和恶性造血细胞以多种方式相互作用，只有少数几种方式被详细描述。破坏MPN SC的绝缘以克服休眠，干扰有利于MPN细胞的异常细胞因子电路，以及直接促进剩余的正常HSC，是扭转平衡有利于正常造血的潜在策略。虽然根除恶性细胞克隆仍然是治疗的目标，但在短期内，重新平衡生态系统可能是一个更容易实现的目标。虽然急性和慢性炎症可导致正常造血干细胞的丧失并导致造血衰竭，但它们对骨髓增生性肿瘤干细胞(MPN SCs)的影响相反，从而推动向髓系恶性肿瘤的进展。赵和Deininger综述了目前对MPN SCs保持休眠以避免干细胞耗竭的机制的理解，这可能为MPN细胞增殖的非细胞还原控制提供见解。
Chronic or recurrent episodes of acute inflammation cause attrition of normal hematopoietic stem cells (HSCs) that can lead to hematopoietic failure but they drive progression in myeloid malignancies and their precursor clonal hematopoiesis. Mechanistic parallels exist between hematopoiesis in chronic inflammation and the continuously increased proliferation of myeloid malignancies, particularly myeloproliferative neoplasms (MPNs). The ability to enter dormancy, a state of deep quiescence characterized by low oxidative phosphorylation, low glycolysis, reduced protein synthesis, and increased autophagy is central to the preservation of long-term HSCs and likely MPN SCs. The metabolic features of dormancy resemble those of diapause, a state of arrested embryonic development triggered by adverse environmental conditions. To outcompete their normal counterparts in the inflammatory MPN environment, MPN SCs co-opt mechanisms used by HSCs to avoid exhaustion, including signal attenuation by negative regulators, insulation from activating cytokine signals, anti-inflammatory signaling, and epigenetic reprogramming. We propose that new therapeutic strategies may be derived from conceptualizing myeloid malignancies as an ecosystem out of balance, in which residual normal and malignant hematopoietic cells interact in multiple ways, only few of which have been characterized in detail. Disrupting MPN SC insulation to overcome dormancy, interfering with aberrant cytokine circuits that favor MPN cells, and directly boosting residual normal HSCs are potential strategies to tip the balance in favor of normal hematopoiesis. Although eradicating the malignant cell clones remains the goal of therapy, rebalancing the ecosystem may be a more attainable objective in the short term. While acute and chronic inflammation can cause loss of normal hematopoietic stem cells and lead to hematopoietic failure, they have an opposite impact on myeloproliferative neoplasm stem cells (MPN SCs), driving progression to myeloid malignancy. Zhao and Deininger review the current understanding of the mechanisms by which MPN SCs preserve dormancy to avoid stem cell exhaustion, which may provide insight for noncytoreductive control of MPN cell proliferation.
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