Beyond VEXAS and UBA1: Identification of Novel Drivers of MDS Autoimmune Syndromes
Abstract
Background: Myelodysplastic syndrome (MDS) is a common form of bone marrow failure that causes increased morbidity and mortality. Both the underlying mechanism and prognosis of MDS have been attributed to specific driver gene mutations that have led to distinct clinical subgroups and differential treatments. MDS frequently cooccurs with autoimmune diseases (rheumatoid arthritis, vasculitis) and this subset has not been evaluated for genetic causes. We recently identified a new genetic cause of MDS with co-occurring inflammation, namely UBA1 and VEXAS syndrome, which has led to changes in treatment, prognosis, and screening. We propose here to expand beyond UBA1 and characterize the genetics, clinical manifestations, and mechanism of such MDS-autoimmune diseases to help find additional subgroups. Together our work will provide insights not only into UBA1 but also general mechanisms found broadly in MDS. Critical Questions: Are there distinct genetic causes and mechanisms underlying MDS-Autoimmune syndromes? Do these genetic alterations lead to unique clinical manifestations and treatment responses? Specific BMF Disease: We will study a subtype of MDS with co-occurring autoimmune diagnoses. These patients encompass 30% of total patients with MDS and have not previously been systematically evaluated. Bone Marrow Failure Research Program (BMFRP) Objective: The work proposed here fulfills the BMFRP objective to understand acquired bone marrow failure syndromes, particularly MDS-autoimmune overlap syndromes such as VEXAS and VEXAS-like diseases. Innovation: Current genetic studies in MDS have primarily focused on sequencing a small subset of genes previously implicated in blood cancers (about 40-80 genes of the 20,000 total genes) for mutations. In addition, in some cases, MDS studies have excluded patients with overlapping rheumatologic diagnoses due to potential confounding causes for blood abnormalities (since rheumatologic diseases can lead to low blood counts on their own), thus potentially missing patients with MDS-autoimmune overlap syndromes such as VEXAS syndrome. These limitations have led to (1) a failure to identify new genetic drivers of MDS since efforts have focused on known genes, and (2) a lack of characterization of MDS-autoimmune overlap diseases. My lab will systematically overcome these limitations to uncover and evaluate somatic and germline variants in MDS-autoimmune overlap syndrome patients. We will compare the clinical profile of patients with specific mutations and try to determine if there are unique clinical manifestations that can be used to help provide improved care for patients. In addition, I plan to extend beyond just finding somatic mutations by determining why these mutant cells lead to bone marrow disease in patient cells and in vitro. For these studies we will use cutting edge approaches to determine the signaling in mutant versus wildtype cells and compare profiles between MDS, MDS-Autoimmune diseases, and healthy controls. Impact: Identification and detailed characterization of genetic drivers of the autoimmune subtype of MDS, in particular UBA1 and VEXAS syndrome, has already led to improved clinical care and new insights into acquired bone marrow failure. Identification of UBA1 has provided diagnoses for thousands of individuals within a short period of time and has led to curative bone marrow transplants and prospective clinical trials. We expect that further genetic studies in this previously overlooked cohort will uncover clinically important associations, have direct benefits for patients in terms of diagnosis and treatment, and will provide the basis for a molecular understanding of disease. Our in vitro and in vivo studies of the role of specific cell types and mutations into disease will help provide key insights into disease pathogenesis and provide potential targets for treatment approaches.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310507
Entities
People
- David Beck
Organizations
- Grossman School of Medicine
- United States Army