Myelodysplasia in VEXAS syndrome.

abstractVEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome is a clonal hematoinflammatory disorder affecting older, predominantly male patients, characterized by systemic inflammation and progressive bone marrow failure. It is caused by somatic mutations in ubiquitin-activating enzyme E1 (UBA1), an X-linked gene, essential for initiating cellular ubiquitination. Loss-of-function mutations, most commonly M41 missense variants, lead to decreased expression of the cytoplasmic isoform, UBA1b, resulting in accumulation of misfolded proteins and activation of the endoplasmic reticulum stress pathway. Patients classically present with systemic and often refractory inflammation, requiring chronic glucocorticoid treatment and targeted immunosuppressive therapies. A central hallmark of this syndrome is progressive bone marrow failure and associated cytopenia, with a diagnosis of myelodysplastic syndromes (MDS) being reported in ∼30% to 50% of patients, whereas only 1% of unselected patients with MDS have UBA1 mutations. This review examines current literature on distinct MDS features reported in VEXAS syndrome. We first summarize the defects and alterations in the hematopoietic system from UBA1 mutations, including associated peripheral blood and bone marrow findings. Next, we describe the histologic and molecular characteristics of patients with VEXAS syndrome, with and without MDS, and review potential treatment strategies, including responses to hypomethylating agents. Finally, we highlight that VEXAS-associated MDS is a challenging diagnosis but one with unique clinical, laboratory, and morphologic features, including prognostic implications.