Molecular pathology selected abstracts

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Molecular association between VEXAS syndrome and clonal hematopoiesis

VEXAS syndrome is characterized by widespread inflammation throughout the body. It is caused by somatic mutations in the UBA1 gene (UBA1^mut ), which is located on the X chromosome. The mutations are passed down in the myeloid lineage and activate inflammatory pathways, leading to severe systemic inflammatory symptoms. Those diagnosed with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome are more likely to develop hematologic malignancies, such as myelodysplastic syndrome and plasma cell dyscrasias. Clonal hematopoiesis is a common age-related phenomenon characterized by the expansion of hematopoietic stem and progenitor cells harboring somatic mutations. The frequency and medical significance of concurrent clonal hematopoiesis mutations and UBA1 mutations in VEXAS have yet to be determined. The authors conducted a study to define the clonal hematopoiesis landscape and how it affects patients with VEXAS syndrome, using error-corrected and single-cell DNA sequencing, and correlated these findings with clinical outcomes. They retrospectively screened 80 patients with VEXAS for clonal hematopoiesis mutations. Sixty percent of patients had typical myeloid mutations that co-occurred with the UBA1 mutations associated with VEXAS. Furthermore, approximately half of the patients exhibited somatic mutations in two or more myeloid genes, which suggests that these people have a higher likelihood of developing mutant clones. The mutations primarily consisted of DNMT3A and TET2 and were detectable in about 50 percent of patients. However, the authors also observed somatic mutations in traditional myelodysplastic syndrome-associated genes, such as TP53, KRAS, NRAS, SF3B1, STAG2, and IDH2. The variant allele frequencies for UBA1 mutations consistently indicated that UBA1 was the dominant clone in hematopoiesis. The mean variant allele frequencies for other mutant myeloid genes ranged from 27 percent for DNMT3A to less than 1.5 percent for TET2. Analysis of DNA at the single-cell level showed clear patterns of clonality. The mutations in DNMT3A occurred primarily before the UBA1 mutation, indicating that the UBA1 mutation occurred in the context of clonal hematopoiesis driven by DNMT3A. TET2 and other genes predominantly manifested as UBA1-mutant subclones or separate clones. The study suggests that DNMT3A and TET2 mutations may contribute to inflammation and propagate it in people with VEXAS. These clones, often found in conjunction with clonal hematopoiesis with UBA1 mutations, promote inflammation and immune cell activation. This study establishes the foundation for a more comprehensive understanding of how DNMT3A and TET2 mutations and other myeloid drivers play a role in UBA1-mutant clones developing into myeloid malignancy. The study supports UBA1 causing myeloid clonal expansion and inflammatory and hematologic phenotypes in VEXAS.

Gutierrez-Rodrigues F, Kusne Y, Fernandez J, et al. Spectrum of clonal hematopoiesis in VEXAS syndrome. Blood. 2023;42(3):244–259.

Correspondence: Dr. Bhavisha A. Patel at bhavisha.patel@nih.gov