Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche.
Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche.
复制标题
作者：
Liu C;Chen Q;Shang Y;Chen L;Myers J;Awadallah A;Sun J;Yu S;Umphred-Wilson K;Che D;Dou Y;Li L;Wearsch P;Ramírez-Bergeron D;Beck R;Xin W;Jin G;Adoro S;Zhou L
内质网未折叠蛋白反应(UPR)是内质网稳态中的一种保守的适应性信号，在高增殖细胞和急性T淋巴细胞白血病(T-ALL)的潜在治疗靶点中发挥着重要作用。方法：在这项研究中，我们评估了T-ALL移植小鼠的骨髓内皮细胞(ECs)和T-ALL患者的骨髓标本中UPR反应的转录和表型变化。我们使用PERK抑制剂和建立内皮细胞特异性PERK基因敲除小鼠来研究PERK对白血病进展和造血的影响。我们采用染色质免疫沉淀(ChIP)技术研究ATF4对JAG1的调控机制。我们鉴定了白血病发育小鼠的小细胞外小泡(SEV)，并研究了SEV对EC功能的影响。结果：我们发现T-ALL的发展诱导了在骨髓内皮细胞血管壁龛中以蛋白激酶RNA样内质网状激酶(PERK)为主的UPR的强烈激活。PERK-eIF2a-ATF4轴的激活重塑了血管生态位，上调了血管生成因子α和ATF4调节的JAG1值，抑制了干细胞因子和CXCL12的表达，而后者对造血干细胞的维持和再生具有重要作用。此外，靶向内皮PERK显著改善了T-ALL的结果。EC特异性的PERK基因缺失取消了异常的JAG1上调，改善了HSC的维持，促进了白血病细胞的凋亡，并提高了总的存活率。最后，我们证明了细胞外小泡是白血病中内皮细胞perk-eIF2a-ATF4激活和JAG1上调的关键介质。动物模型研究证实，PERK-ATF4-JAG1在人类T-ALL骨髓和T-ALL异种移植中显著激活。结论：我们的研究首次揭示了白血病启动的PERK-ATF4-JAG1轴在骨髓血管龛重构中起关键作用，靶向血管龛UPR是T-ALL潜在的治疗机会。
The endoplasmic reticulum unfolded protein response (UPR) is a conserved adaptive signaling in ER homeostasis and has emerged as critical in highly proliferating cells and potential treatment target for acute T-cell lymphoblastic leukemia (T-ALL). Methods: in this study, we assessed the transcriptomic and phenotypic alterations in UPR response of the bone marrow endothelial cells (ECs) in mice engrafted with T-ALL and in bone marrow specimens from patients who have T-ALL. We used PERK inhibitor and generated endothelial specific PERK knockout mice to study the impact of PERK on leukemia progression and hematopoiesis. We performed chromatin immunoprecipitation (ChIP) to study the mechanistic regulation of JAG1 by ATF4. We characterized small extracellular vesicles (SEV) from leukemia-developing mice and studied the effect of SEVs on EC function. Results: we found that T-ALL development induced a robust activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dominant UPR in the bone marrow endothelial vascular niche. The activation of PERK-eIF2a-ATF4 axis remodels the vascular niche, upregulates angiogenic factors including VEGFα and ATF4-regulated JAG1, and suppresses the expression of SCF and CXCL12, which are important to HSC maintenance and regeneration. Further, targeting endothelial PERK significantly improved T-ALL outcome. EC-specific deletion of PERK abolished the aberrant JAG1 up-regulation, improved HSC maintenance, promoted leukemia apoptosis, and improved overall survival. Finally, we showed that small extracellular vesicles are critical mediators of endothelial PERK-eIF2a-ATF4 activation and JAG1 up-regulation in leukemia. Corroborating animal model studies, activation of PERK-ATF4-JAG1 is prominent in human T-ALL bone marrow and T-ALL xenografts. Conclusion: our studies thus revealed for the first time that the leukemia-initiated PERK-ATF4-JAG1 axis plays a critical role in the remodeling of the bone marrow vascular niche and that targeting vascular niche UPR is a potential therapeutic opportunity in T-ALL.
登录
查看更多内容
影响因子：
11.4
作者：
Huiting LN;Samaha Y;Zhang GL;Roderick JE;Li B;Anderson NM;Wang YW;Wang L;Laroche F;Choi JW;Liu CT;Kelliher MA;Feng H
通讯作者：
Feng H
影响因子：
11.2
作者：
Jeon HM;Kim SH;Jin X;Park JB;Kim SH;Joshi K;Nakano I;Kim H
通讯作者：
Kim H
影响因子：
4.8
作者：
Khan, MM;Nomura, T;Ishii, S
通讯作者：
Ishii, S
肌动蛋白动力学通过调节真核起始因子2α去磷酸化来调节综合应力反应。
影响因子：
7.7
作者：
Chambers JE;Dalton LE;Clarke HJ;Malzer E;Dominicus CS;Patel V;Moorhead G;Ron D;Marciniak SJ
通讯作者：
Marciniak SJ
影响因子：
64.5
作者：
Benedito, Rui;Roca, Cristina;Adams, Ralf H.
通讯作者：
Adams, Ralf H.