Researchers have discovered a previously unknown role of p53 in VEXAS syndrome physiopathology, according to research presented at the 66th American Society of Hematology Annual Meeting and Exposition.
VEXAS syndrome is an autoinflammatory disorder caused by mutations that occur in the UBA1 gene. UBA1 is a key enzyme of protein ubiquitylation that plays a role in the post-translational regulation of various proteins.
Olivier Hermine, MD, PhD, of Necker-Enfants Malades Hospital in Paris, and colleagues hypothesized that UBA1-mutated erythroblasts may generate pathologic red blood cells (RBCs) that are responsible for the macrocytic anemia seen with VEXAS and may contribute to systemic inflammation through erythrophagocytosis.
To explore this, the researchers used blood and marrow samples taken from eight patients with VEXAS at Paris hospitals. Using mass spectrometry-based proteomics, the researchers quantified absolute copy number for total erythrocyte proteomes. They then analyzed erythropoiesis from peripheral blood and cord blood CD34-positive cells and Hudep-2 erythroid cell line.
Compared with eight age-matched controls, the RBCs from patients with VEXAS did not have significant differences in mean projected surface area, lactadherin staining, mitochondrial retention or deformability, and polyubiquitin content.
Dr. Hermine and colleagues also found that UBA1 pathogenic variants were present in patients’ non-erythroid bone marrow cells, but not in polychromatophilic or orthochromatophilic erythroblasts.
Knocking-in of the p.Met41Thr variant (p.M41L) led to massive lethality in the proerythroblastic Hudep-2 cell line and in cord blood CD36+ erythroid cultures. Finally, there was no massive lethality in cord blood CD36-negative monocytic or macrophagic cultures.
In vitro erythropoiesis using peripheral blood CD34-positive cells indicated clearance of UBA1 pathogenic variants, and generated mature erythroblasts were UBA1 negative.
Editing two days after isolation showed that ubiquitylation of p53 was defective in base-edited cells in TUBE capture and immunoprecipitation assays, and that p53 was markedly overexpressed six days after base editing at an early stage of erythroid differentiation and two days before cell death onset.
Taken together, “we found that cytosolic UBA1 is critical for adequate TP53 ubiquitylation and ribosomal biogenesis,” Dr. Hermine said. “TP53 accumulation might be due to this ubiquitylation defect and/or ribosomal biogenesis impairment and HDM2 inhibition, which increases expression of p53.”
Therefore, VEXAS-causing UBA1 variants result in massive cell death at the early stage of erythroid differentiation, a result that explains the absence of these variants in patients’ erythroid marrow precursors and the absence of pathologic features in circulating RBCs.
Finally, the researchers found that UBA1-mutated cells were “quite sensitive to bortezomib; both the erythroid compartment by itself was sensitive to this mutation, and myeloid, which is responsible for inflammation, might also be sensitive to bortezomib.”
“We may see that VEXAS is a new ribosomopathy like most [Diamond-Blackfan anemia],” Dr. Hermine concluded.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Rodriques F, Hardouin G, El Hoss S, et al. Vexas syndrome is a new cause of p53-mediated erythroblastopenia. Abstract 36. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.
