The recently discovered VEXAS syndrome (Vacuoles in myeloid progenitors, E1 ubiquitin ligase, X-linked, Auto-inflammatory manifestations and Somatic) is the consequence of the clonal expansion of hematopoietic stem or progenitor cells with somatically acquired mutations in UBA1 gene, which encodes for a key enzyme of the ubiquitylation proteasome system (UPS) [1]. Most of the mutations described so far concern directly the translation initiation site of UBA1b (Met 41) or alter the splicing of intron 2 splicing. These mutations lead to the expression of a shorter cytoplasmic isoform of UBA1 in myeloid cells and result in uncontrolled inflammation [1]. Unleashed inflammation is thought to be primarily due to accumulation of misfolded proteins that are not properly directed to the proteasome for degradation and activate the unfolded protein response (UPR). Clinically, the disease is defined by non-specific and highly heterogeneous inflammatory manifestations. Additionally, VEXAS syndrome hallmarks are progressive cytopenia, predominantly macrocytic anemia. Altogether, VEXAS syndrome is a unique acquired hematological monogenic disease characterized by auto-inflammatory manifestations, specific dysplastic features and association with hematological neoplasms. Since VEXAS discovery in 2020, great efforts have been made to define, harmonize and understand this multi-faceted disease. While the defect originates in the hematopoetic progenitor cells, patients with VEXAS primarily present with wide spread inflammation affecting nearly any organ and may have cytopenia with disease progression [add Obiorah paper citation]. Thus, treating physicians involved in VEXAS patients care are highly diverse and range from rheumatologists, dermatologists, and in later stages, hematologists.

The goal of this review is to depict VEXAS syndrome from a hematological point of view regarding its consequences on hematopoiesis and the current strategies on therapeutic interventions.