New insights into the pathomechanism of cyclic neutropenia
New insights into the pathomechanism of cyclic neutropenia
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DOI：
10.1111/nyas.14309
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发表时间：
2020-02-21
影响因子：
5.2
通讯作者：
Welte, Karl
中科院分区：
文献类型：
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作者：
Mir, Perihan;Klimiankou, Maksim;Welte, Karl
周期性中性粒细胞减少症（CyN）是一种血液疾病，其中外周血中性粒细胞绝对计数（ANC）显示约21天间隔的周期。大多数CyN患者携带ELANE突变，但ANC循环的机制尚不清楚。我们在ANC周期的峰值和最低点对CyN患者的骨髓（BM）亚群进行了分析，并在ANC周期的最低点检测到BM造血干细胞（HSC）和造血干细胞和祖细胞（HSPC）的高比例，与峰值相比。BM HSPC在ANC峰值时产生较少的粒细胞集落形成单位集落。为了研究循环的机制，我们发现ELANE和未折叠蛋白反应（UPR）相关基因（ATF 6，BiP（HSPA 5），CHOP（DDIT 3）和PERK（EIF 2AK 3））的mRNA表达水平升高，但在ANC最低点测试的CD 34（+）细胞中抗凋亡基因（Bcl-2（BCL 2）和bcl-xL（BCL 2L 1））降低。此外，HSPC显示在ANC最低点时活性氧和gH 2AX水平增加。我们认为，在CyN患者中，一些HSPCs逃避UPR诱导的内质网（ER）应激，并响应于粒细胞集落刺激因子（G-CSF）增殖到一定的阈值，在该阈值下，UPR再次影响大多数HSPCs。在ER应激诱导的HSPC凋亡和G-CSF刺激的HSPC代偿性增殖以及随后的粒细胞分化之间存在循环平衡。
Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34(+) cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.