image: Figure 1: Conceptual representation of the differential effect of UBA1 mutations based on the degree of loss of function of ubiquitin E1 enzyme UBA1. (left panel) UBA1, an E1 enzyme, activates ubiquitin and subsequently transfers the activated ubiquitin to up to approximately 30 E2 enzymes with various efficiency. The displayed heatmap illustrates the variability in ubiquitin transfer efficiency (dark green: low efficiency, brown: high efficiency) of UBA1 wild type (first column), UBA1 partial loss of function (second column) and UBA1 total loss of function (third column). Wild type UBA1 and partial loss of function mutations affect the ubiquitin transfer efficiency of a subset of E2 enzymes, whereas a total loss of function of UBA1 leads to a complete loss of loading of ubiquitin to E2 enzymes solely dependent on UBA1. (right panel) At the E2/E3-substrate transfer step, the effect of UBA1 loss of function is mediated by the decrease of available ubiquitin-loaded E2 enzymes. In the case of partial loss of function mutations, ubiquitylation of substrates can be variable due to the differential impairment of ubiquitin transfer to the E2 enzymes, which may result in imbalance of regulator proteins and altered cell fate.
Credit: 2024 Sakuma et al.
“Ultimately, a thorough grasp of the pathogenesis of VEXAS, from genetic mutations to clinical manifestations, will be pivotal in devising safe and effective therapeutic strategies to fight this challenging disease.”
BUFFALO, NY- October 3, 2024 – A new research perspective was published in Oncotarget's Volume 15 on September 30, 2024, entitled, “UBA1 dysfunction in VEXAS and cancer.”
As highlighted in the abstract of this paper, UBA1 is an X-linked gene that encodes one of the only two ubiquitin E1 enzymes and plays a pivotal role in initiating one of the most essential post-translational modifications. In late 2020, partial loss-of-function mutations in UBA1 within hematopoietic stem and progenitor cells were found to be responsible for VEXAS Syndrome, a previously unidentified hematoinflammatory disorder that predominantly affects older males. This condition is characterized by severe inflammation, cytopenias, and an association with hematologic malignancies.
In their paper, researchers Maki Sakuma, Torsten Haferlach, and Wencke Walter from MLL Munich Leukemia Laboratory and the Medical Graduate Center at Technical University Munich comprehensively review the molecular significance of UBA1 loss of function, along with advancements in VEXAS research over the past four years. The review covers each of the VEXAS manifestations, including inflammation, cytopenias, clonality, and potential oncogenicity.
They also explore the therapeutic landscape for VEXAS Syndrome, and detail the efficacy and potential of clone-targeting drugs based on the pathobiology of VEXAS.
“Ultimately, a thorough grasp of the pathogenesis of VEXAS, from genetic mutations to clinical manifestations, will be pivotal in devising safe and effective therapeutic strategies to fight this challenging disease.”
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28646
Correspondence to: Wencke Walter - wencke.walter@mll.com
Keywords: cancer, VEXAS, MDS, clonal cytopenia, ubiquitin, inflammation
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Journal
Oncotarget
Method of Research
News article
Subject of Research
Not applicable
Article Title
UBA1 dysfunction in VEXAS and cancer
Article Publication Date
30-Sep-2024
COI Statement
TH declares part ownership of the MLL Munich Leukemia Laboratory. MS and WW are employed by the MLL Munich Leukemia Laboratory.