Thanks Pedro!!!

Also thanks to Ian Demsky @mskcancercenter.bsky.social for this fantastic article on our paper:

www.mskcc.org/news/msk-res...

Elisa de Stanchina and her amazing team, key collaborators in
@caleblareau.bsky.social and @lowelab.bsky.social
and support from funders at NIH, Burroughs Wellcome Fund, Ludwig Center at MSK, @cycleforsurvival.bsky.social
@wcm-imp.bsky.social
@mskcancercenter.bsky.social
- THANK YOU ALL! 13/

It's been an absolute whirlwind working on this project from start to finish and a ton of fun! So many people to thank including Linsey Wierciszewski, Pia Martindale (who both started my lab with me in 2022!), Rebecca Londoner, @joshuakmorrison.bsky.social, Yuzu Kanno, Alek Casiano,... 12/

And finally, molecularly, this cell death phenotype correlated with a marked kinetic defect in the Lys63/Linear polyubiquitylation of inflammatory signaling complexes, linking VEXAS with other rarer germline disorders affecting LUBAC, OTULIN, etc 11/

Secondly, Uba1 M41T mutation either in mouse or human HSPCs triggered a pronounced myeloid bias and an unfolded protein response, as described in the initial NEJM report - notably, this was independent of cell death as it still occurred in RIPK3-Casp8 deficient mutant cells 10/

First, we found that across all mutation types tested (M41T, M41V, splice site mutants), Uba1 mutant macrophages showed aberrant apoptotic and necroptotic responses to stimulation with inflammatory triggers like TNF and LPS - through the RIPK3-MLKL-Casp8 axis. 9/

This worked surprisingly well in pools of primary macrophages and we even saw the VEXAS-like diminution of UBA1b and expression of UBA1c, so we were off to the races to try to figure out what was happening molecularly/cellularly. 8/

So, we ultimately recreated Uba1 M41T, M41V, and splice site mutations (which happen to lead to a mis-splicing event that skips Met41) in primary mouse macrophages as well as M41T mutations mouse HSPCs, human monocytes and HSPCs! 7/

But how do you connect UBA1 mutations to this severe autoinflammatory phenotype? This is where Varun and @tandriladas.bsky.social stepped in. The first key step was developing robust genetic models. 6/

Strikingly, Beck et al found that these somatic mutations occurred in hematopoietic stem/progenitor cells (HSPCs) and their myeloid, but not lymphoid, progeny - leading to progressive bone marrow failure and severe multiorgan autoinflammation. 5/

So what are these mutations? Beautiful work from Beck et al in the NEJM paper showed Met41 mutations selectively impair translation initiation that normally generates the UBA1b isoform, leading to aberrant initiation at Met67 instead - generating an impaired isoform, UBA1c. 4/

Fast forward several years, and what's emerged is that this unusual disease termed VEXAS syndrome for its cardinal features has an estimated prevalence as high as ~1 in 4,000 males over 50 3/

pubmed.ncbi.nlm.nih.gov/36692560/

The story begins in Dec 2020, when a group at NIH
discovered somatic mutations in UBA1 - initially all at Met41 - in 25 patients with an undiagnosed inflammatory/hematologic disorder. A real shock as UBA1 is the major E1 enzyme in the ubiquitylation cascade! 2/

pubmed.ncbi.nlm.nih.gov/33108101/

Deep thanks to our many collaborators and all research participants. #immunology #science 🧪 @science.org @sarahhross.bsky.social

NIH funding was the lifeblood of this work, as it is for almost all biomedical discoveries and therapies in the U.S. @niaidnews.bsky.social