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展开的蛋白质响应信号促进髓状细胞的产生,并与瘤基因突变合作

Hyunjoo Choi¹, Sang-Eun Jung¹, Hyojung Paik²

¹Division of Hematology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.

bioRxiv : the preprint server for biology

|September 18, 2025

概括

展开的蛋白质反应 (UPR) 调节了造血干细胞的命运,促进了骨髓质而不是红细胞的产生. 通过与JAK2突变合作,UPR信号加剧了多细胞真血症.

科学领域:

血液学血液学血液学
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

展开的蛋白质反应 (UPR) 是一种细胞应激反应,对维持蛋白质平衡至关重要.
UPR信号在各种生理过程中起作用,包括新陈代谢,癌症和免疫学.
最近的研究强调了UPR在造血干细胞和祖细胞生物学中的参与,但其在血统命运决定中的作用尚不清楚.

研究的目的:

调查UPR信号在造血系命运决定中的作用.
为了确定UPR信号如何影响髓状和红状腺细胞的产生.
探索UPR信号在JAK2突变和多细胞血病真实背景下的影响.

主要方法:

使用具有JAK2V617F突变的小鼠模型.
分析了造血干细胞和原始细胞种群,特别是FcγR-MPP3.
研究了UPR通路的参与,包括XBP1和ATF4.
在健康的捐赠者和多细胞血症患者骨髓细胞中比较了UPR激活效应.

主要成果:

UPR信号促进FcγR-MPP3向GMP的转换,通过XBP1通路增加骨髓细胞的产生,而牺牲了红色细胞的血统.
在多细胞血症真菌小鼠模型中,UPR信号与JAK2V617F突变合作,通过ATF4通路加剧了红细胞形成.
在健康的骨髓MPP细胞中,UPR激活增加了髓状细胞的输出,但在PV患者的MPP细胞中,产出偏向了红状腺血统.

结论:

UPR信号在确定造血系命运方面发挥着新的作用.
UPR的激活会影响骨髓和红状腺细胞的产生.
准UPR信号可能为血液性恶性瘤提供治疗潜力,如真多细胞血症.

关键词:

造血干细胞 (HSC) 是一种血液形成干细胞.杰克2V617FF 在线播放红色素质的人类形成.多能原始体 (MPP) 是一种多能原始体.骨髓形成 (myelopoiesis) 是一种形成骨髓的过程.维拉多细胞血症维拉多细胞血症不折叠的蛋白质反应反应

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