Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome

"Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown."

"Here, we employ somatic gene editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. In contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-Caspase-8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kine"

Somatically acquired UBA1 mutations within hematopoietic stem and progenitor cells (HSPCs) cause VEXAS and drive clonal expansion in myeloid but not lymphoid compartments. Somatic gene editing approaches modeled VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL. In mice challenged with TNF or LPS, UBA1 inhibition by TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. Uba1 mutation in HSPCs triggered an unfolded protein response and promoted a myeloid differentiation bias independently of RIPK3-Caspase-8. Aberrant macrophage death coincided with dysregulated inflammatory signaling that contributes to multiorgan autoinflammation and hematologic disease.

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