VEXAS-Associated MDS Is ‘Distinct’ From Classical MDS

By Cecilia Brown - Last Updated: May 3, 2023

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)-associated myelodysplastic syndrome (MDS) is “distinct from classical MDS in its presentation and clinical course,” according to a recent study.

Fernanda Gutierrez-Rodrigues, PhD, of the National Heart, Lung, and Blood Institute and colleagues conducted the research and published their findings in Blood.

VEXAS, which is caused by somatic mutations in UBA1 and is “characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations,” meets criteria for MDS and plasma cell dyscrasias, they wrote. However, the “landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis in these patients is unknown,” according to the study’s authors.

Dr. Gutierrez-Rodrigues and colleagues retrospectively screened 80 patients with VEXAS for clonal hematopoiesis in their peripheral blood and correlated findings with clinical outcomes in 77 patients.

UBA1 mutations were most common at the “hotspot” encoding methionine-41 with a median variant allele frequency of 75%. They also found that typical clonal hematopoiesis mutations in genes such as DNMT3A and TET2 co-occurred with UBA1 mutations in 60% of patients. However, those were not associated with “inflammatory or hematologic manifestations,” Dr. Gutierrez-Rodrigues and colleagues wrote.

Prospective single-cell proteogenomic sequencing showed mutated UBA1 was the “dominant” clone and was “present mostly in branched clonal trajectories,” according to the study’s authors.

The researchers identified two major patterns of clonality in VEXAS based on integrated bulk and single-cell proteogenomic sequencing. One of the clonality patterns showed “typical” clonal hematopoiesis preceding selection of mutated UBA1 in a clone. The second pattern showed clonality occurring as a mutated UBA1 subclone or in independent clones.

The 10-year overall survival rate was 60% for all patients, with transfusion-dependent anemia, moderate thrombocytopenia, and typical clonal hematopoiesis mutations each correlating with a “poor outcome,” the study’s authors wrote.

“In VEXAS, UBA1-[mutated] cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS,” the study’s authors wrote. “VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.”


Gutierrez-Rodrigues F, Kusne Y, Fernandez J, et al. Spectrum of clonal hematopoiesis in VEXAS syndrome. Blood. 2023. doi:10.1182/blood.2022018774

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