MSK Researchers Make Strides Against VEXAS Syndrome

Researchers at Memorial Sloan Kettering Cancer Center (MSK) have developed some of the first robust laboratory models of a confounding adult-onset inflammatory disease called VEXAS syndrome — shedding new light on its mechanisms and laying the groundwork for potential targeted treatments.

The research — led by the study’s co-first authors Varun Narendra, MD, PhD, a physician-scientist specializing in leukemia, and Tandrila Das, PhD, a research scholar, and senior author Alexander Gitlin, MD, PhD — drew on MSK’s expertise in immunology and blood disorders.

The team’s findings, which were published November 3 in Nature, revealed new insights about the disease’s two core problems:

• First, a mutation in the UBA1 gene pushes blood-forming stem cells in the bone marrow to produce too many myeloid cells, a type of immune cell.
• Second, descendants of these cells that become macrophages are hypersensitive to danger signals, causing them to self-destruct and send out alarm signals — which may fuel a feedback loop that draws more of these defective immune cells, which in turn also implode, releasing a new wave of danger signals.

The team also mapped the molecular circuitry that makes these mutant cells overreact — and showed in mouse models that blocking parts of this “death axis” can dampen the inflammation cycle driving the disease.

“There currently aren’t any targeted treatments for VEXAS syndrome,” says Dr. Gitlin, an immunologist at MSK’s Sloan Kettering Institute. “We are hopeful that the therapeutic targets identified by our research can pave the way for new approaches.”

The study was conducted in collaboration with the labs of MSK’s Caleb Lareau, PhD, and Scott Lowe, PhD.

VEXAS: A Vexing Disease That Primarily Affects Older Men

VEXAS wasn’t identified until 2020, when a team of researchers from the National Institutes of Health looked for genetic variants in patients with unexplained and severe inflammatory symptoms. Among these patients, the NIH group identified an unexpected mutation in the UBA1 gene — now recognized as the cause of VEXAS.

For most patients with VEXAS, the trouble starts with a tiny DNA change at position 41 on the UBA1 gene, where the normal methionine molecule is replaced by a different amino acid.

This single genetic “typo” can cause a variety of symptoms throughout the body, including recurring fevers, low blood counts, painful skin rashes, blood clots, shortness of breath, headaches, and extreme fatigue.

Continuing research showed VEXAS is more widespread than was first realized — affecting up to 1 in 4,000 men over age 50 worldwide.

VEXAS primarily affects older people because it arises from a spontaneous DNA mutation — rather than an inherited one — and the older people get, the more of these “somatic” mutations arise in their genetic code. And it affects mostly men because the UBA1 gene is located on the X chromosome. Men have only one copy of the X chromosome, whereas women have two, leaving them a “backup” copy if a mutation occurs.

(VEXAS stands for the syndrome’s notable characteristics: vacuoles, E1 enzyme, X linked, autoinflammatory, somatic.)

Why Study VEXAS at a Cancer Center?

VEXAS isn’t cancer, but the autoinflammatory disease shares some important features with blood cancers — making MSK a logical place to study it.

Like many blood cancers, VEXAS begins with a mutation in blood-forming stem cells and progenitor cells, and then these mutated clones become dominant over time — to the detriment of normal bone marrow and blood cells. The overproduction of myeloid cells is also seen in some blood cancers.

The big difference between VEXAS and cancer is that VEXAS is characterized by overwhelming immune dysregulation and excessive inflammatory cell death.

The Precision Tools Needed to Understand VEXAS

Because the mutation that causes VEXAS is so small and precise, studying VEXAS in the laboratory has been extremely challenging. The MSK team used a CRISPR-like tool known as “base editing” to swap one DNA letter for another at exactly the right spot in both mouse and human cells — creating some of the first robust models to study the mechanisms of the disease.

“Many people have heard of CRISPR-Cas9, the Nobel-winning gene editing tool, which lets scientists make insertions or deletions within the genetic code. This is a sister technology that allows you to introduce point mutations that basically change just one letter of the genetic code,” Dr. Narendra says. “As a physician and researcher who specializes in leukemia and myelodysplastic syndromes, I’ve been working for some time to apply this type of base editing to cells in the hematopoietic, or blood-making, system so that certain genetic variants can be modeled in the lab.”

Synergy With Immunology Research

It was in studying VEXAS that Dr. Narendra’s interest in developing new hematopoietic models synergized with Dr. Gitlin’s immunology research. Dr. Gitlin’s lab, in MSK’s Immunology Program, studies how cell signaling controls the nature and magnitude of inflammation, which has applications in cancer and other diseases.

Dr. Das and senior research technician Linsey Wierciszewski, both members of the Gitlin Lab, led the biochemical studies that examined what causes these mutant macrophages to self-destruct in an inflammatory way when they encounter an immune alarm signal like TNF (tumor necrosis factor, a cytokine) or LPS (lipopolysaccharide, a molecule whose bacterial origins the immune system recognizes).

“TNF and LPS are the types of signals that macrophages encounter pretty frequently,” Dr. Das says. “But instead of reacting normally, cells carrying the VEXAS mutation die — and they die in a way that is quite inflammatory and that appears to propagate even more inflammation by attracting more of these self-destructing cells.”

Additionally, Dr. Das and Wierciszewski helped map the cell-death signaling pathway whose modulation offers promise for reducing VEXAS-related inflammation: the RIPK1-RIPK3-Caspase-8 axis.

“This research actually traces back to discoveries made at MSK in the 1970s,” Dr. Gitlin says. “TNF, first identified by Lloyd Old and Elizabeth Carswell, was named for its ability to kill tumor cells, but it’s now recognized as a key driver of inflammatory diseases and may, paradoxically, even promote cancer growth in some contexts.”

Not only does the research shed new light on VEXAS, Dr. Gitlin adds. It hints that dysregulated cell death may be a more common cause of inflammatory disease than has been previously appreciated.

Additional Authors, Funding, and Disclosures

Additional authors on the paper include Rebecca Londoner, Joshua Morrison, Pia Martindale, Tessa Devine, Kevin Chen, Michael Trombetta, Yuzuka Kanno, Alejandro Casiano, and Elisa de Stanchina.

The work used the resources of the Integrated Genomics Operation at MSK.

The research was supported by a Burroughs Wellcome Fund Career Award for Medical Scientists, a Cycle for Survival Equinox Innovation Award, the Ludwig Center for Cancer Immunotherapy at MSK, a Josie Robertson Investigator Award, an Edward P. Evans Foundation Young Investigator Award, the Center for Experimental Immuno-Oncology Scholars Program, the American Society of Clinical Oncology Young Investigator Award, Anna Maria and Stephen Kellen Pre-Doctoral Fellowship in Cancer Immunology, the National Heart, Lung, and Blood Institute (1F31HL182193), the National Institute of Allergy and Infectious Disease (R01 AI187249), and the National Cancer Institute (K12 CA184746, 5P50CA254838, P30 CA008748, T32 CA009512).

Read the article: Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome, Nature. DOI: 10.1038/s41586-025-09815-0

Dr. Lowe holds the Geoffrey Beene Chair at MSK and is a Howard Hughes Medical Institute Investigator.

Key Takeaways

• MSK researchers developed some of the first robust laboratory models to study VEXAS syndrome, an autoinflammatory disease that affects 1 in 4,000 men over 50.
• The MSK study sheds new light on the mechanisms of VEXAS and identified new therapeutic targets against it.
• The research also suggests dysregulated cell death may be a more common cause of inflammatory disease than has been previously appreciated.