Early Activation of Inflammatory Pathways in UBA1-mutated Hematopoietic Stem and Progenitor Cells in VEXAS

Overview

Journal Cell Rep Med

Publisher Cell Press

Specialties Biology
General Medicine

Date 2023 Aug 16

PMID 37586319

Authors

Zhijie Wu

Shouguo Gao

Qingyan Gao

Bhavisha A Patel

Emma M Groarke

Xingmin Feng

Ash Lee Manley

Haoran Li

Daniela Ospina Cardona

Sachiko Kajigaya

Lemlem Alemu

Diego Quinones Raffo

Amanda K Ombrello

Marcela A Ferrada

Peter C Grayson

Katherine R Calvo

Daniel L Kastner

David B Beck

Neal S Young

Affiliations

Soon will be listed here.

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a pleiotropic, severe autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. To elucidate VEXAS pathophysiology, we performed transcriptome sequencing of single bone marrow mononuclear cells and hematopoietic stem and progenitor cells (HSPCs) from VEXAS patients. HSPCs are biased toward myeloid (granulocytic) differentiation, and against lymphoid differentiation in VEXAS. Activation of multiple inflammatory pathways (interferons and tumor necrosis factor alpha) occurs ontogenically early in primitive hematopoietic cells and particularly in the myeloid lineage in VEXAS, and inflammation is prominent in UBA1-mutated cells. Dysregulation in protein degradation likely leads to higher stress response in VEXAS HSPCs, which positively correlates with inflammation. TCR usage is restricted and there are increased cytotoxicity and IFN-γ signaling in T cells. In VEXAS syndrome, both aberrant inflammation and myeloid predominance appear intrinsic to hematopoietic stem cells mutated in UBA1.

Citing Articles

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