Gitlin Lab MSK
@GitlinLab_MSK
Assistant Member/Professor, Lab Head @MSKCancerCenter ex-@Genentech @StanfordPath @TriIMDPhD. #PhysicianScientist #Immunologist. Views my own.
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🚨Thrilled to share our latest work, published online today @Nature in which we decipher mechanisms underlying the enigmatic VEXAS syndrome - a huge team effort @MSKCancerCenter led by superstars @VarunNarendraMD + @das_tandrila 🧵1/ nature.com/articles/s4158…
@GitlinLab_MSK we are looking forward to your presentation at our #UbiquitinFunction meeting in Portugal 🇵🇹 Please share this with your followers to let them know you will speaking, and to register & submit today to join us! 🔗bit.ly/489D5LQ
A team at MSK is shedding new light on VEXAS syndrome, a severe autoinflammatory condition arising from a mutation in the UBA1 gene. “There currently aren’t any targeted treatments for VEXAS syndrome,” says Dr. Alexander Gitlin, an immunologist at MSK’s Sloan Kettering Institute…
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/
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/
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/
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/
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/
But how do you connect UBA1 mutations to this severe autoinflammatory phenotype? This is where @VarunNarendraMD @das_tandrila stepped in. The first key step was developing robust genetic models. 6/
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 @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! pubmed.ncbi.nlm.nih.gov/33108101/2/
🚨Thrilled to share our latest work, published online today @Nature in which we decipher mechanisms underlying the enigmatic VEXAS syndrome - a huge team effort @MSKCancerCenter led by superstars @VarunNarendraMD + @das_tandrila 🧵1/ nature.com/articles/s4158…
More on somatic evolution in the blood! Great new work on VEXAS syndrome. Excellent summary thread of a fascinating syndrome and great science to unravel it.
🚨Thrilled to share our latest work, published online today @Nature in which we decipher mechanisms underlying the enigmatic VEXAS syndrome - a huge team effort @MSKCancerCenter led by superstars @VarunNarendraMD + @das_tandrila 🧵1/ nature.com/articles/s4158…
The very first story from the Gitlin lab is out! Some massively cool science done by such an incredible team that I’m very lucky to be a part of.
🚨Thrilled to share our latest work, published online today @Nature in which we decipher mechanisms underlying the enigmatic VEXAS syndrome - a huge team effort @MSKCancerCenter led by superstars @VarunNarendraMD + @das_tandrila 🧵1/ nature.com/articles/s4158…
Excited to see our paper online! Grateful to work in such a collaborative environment @GitlinLab_MSK. Congratulations to all co-authors @VarunNarendraMD, Linsey Wierciszewski, Rebecca Londoner, @joshuakmorrison, @PiaMartindale, Yuzuka Kanno, Alek Casiano!
🚨Thrilled to share our latest work, published online today @Nature in which we decipher mechanisms underlying the enigmatic VEXAS syndrome - a huge team effort @MSKCancerCenter led by superstars @VarunNarendraMD + @das_tandrila 🧵1/ nature.com/articles/s4158…
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