Understanding inflammatory cell death as a driver of VEXAS pathogenesis

/Abstract Somatically acquired mutation in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) was recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic). Most VEXAS-associated mutations occur at Met41 in UBA1 and lead to clonal expansion within the HSPC and myeloid compartments, and frequently cause myelodysplastic syndrome (MDS) in addition to multi-organ inflammation. Despite the severity and prevalence of VEXAS, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and myeloid malignancy are unknown. Our preliminary work utilizes newly developed and genetically controlled primary cell-based models of VEXAS to show that UBA1 mutant HSCs are primed towards myeloid differentiation and that their myeloid progeny undergo aberrant inflammatory cell death upon engagement of innate immune receptors. We hypothesize that aberrant inflammatory cell death underlies VEXAS pathogenesis. To build upon our preliminary work, this career development program will address 2 specific aims: (1) to determine cell-intrinsic and -extrinsic factors that promote clonal expansion and myeloid skew of UBA1 mutant HSPCs, and (2) to evaluate the role of inflammatory cell death as a therapeutic target in VEXAS. The proposed studies are part of the candidate’s developing research program at the intersection of myeloid malignancy and innate immune signaling and build upon his clinical expertise in MDS and AML. Dr. Narendra will develop a research program under the close supervision of his mentor Dr. Alexander Gitlin, an expert in the molecular basis of innate immune signaling, and co-mentor Dr. Scott Lowe, an expert in cancer biology, mouse models and functional genetics. Dr. Narendra will additionally be supported by members of his advisory committee including Drs. Omar Abdel- Wahab, Caleb Lareau, and Alexander Rudensky, experts in experimental and computational approaches to the study of hematopoiesis and immunity. Under the guidance of his mentors and advisory committee, the candidate will continue to gain expertise in immunology, malignant hematopoiesis, and single cell analytics. Dr. Narendra’s training environment will ideally position him to achieve his goal of becoming an independent physician-scientist, working at the convergence of innate immunity and cancer. Project Number: 1K08CA304350-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Varun Narendra | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $294,451 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 CTH-K (83)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11372439