Journal Article

Endothelial PERK-ATF4-JAG1 axis activated by T-ALL remodels bone marrow vascular niche

Wearsch, Pamela, Liu, Cui, Che, Danian, Ramírez-Bergeron, Diana, Yu, Shuiliang, Adoro, Stanley, Xin, Wei, Chen, Qiuyun, Dou, Yingtong, Zhou, Lan, Myers, Jay, Umphred-Wilson, Katharine, Beck, Rose, Shang, Yinghui, Chen, Lechuang, Li, Luoyi, Jin, Ge, Awadallah, Amad, Sun, Jinger

2022

Overview

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). 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. 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. 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.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Activating Transcription Factor 4 - genetics / Activating Transcription Factor 4 - metabolism / Animals / Antibodies / Bone marrow / Bone Marrow - metabolism / Chemotherapy / eIF-2 Kinase - metabolism / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum Stress / Endothelial Cells - metabolism / Extracellular vesicles / Humans / Jagged-1 Protein - genetics / Jagged-1 Protein - metabolism / Jagged-1 Protein - pharmacology / Kinases / Leukemia / Mice / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Proteins / Research Paper / Stem cells / Unfolded Protein Response