Oncotarget

Research Perspectives:

UBA1 dysfunction in VEXAS and cancer

Maki Sakuma, Torsten Haferlach and Wencke Walter _

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Oncotarget. 2024; 15:644-658. https://doi.org/10.18632/oncotarget.28646

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Abstract

Maki Sakuma1,2, Torsten Haferlach1 and Wencke Walter1

1 MLL Munich Leukemia Laboratory, Munich, Germany

2 Medical Graduate Center, Technical University Munich, Munich, Germany

Correspondence to:

Wencke Walter, email: [email protected]

Keywords: VEXAS; MDS; clonal cytopenia; ubiquitin; inflammation

Received: August 05, 2024     Accepted: August 18, 2024     Published: September 30, 2024

Copyright: © 2024 Sakuma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

UBA1, an X-linked gene, encodes one of the only two ubiquitin E1 enzymes, playing 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 predominantly affecting older males. The condition is characterized by severe inflammation, cytopenias, and an association to hematologic malignancies. In this research perspective, we comprehensively review the molecular significance of UBA1 loss of function as well as advancements in VEXAS research over the past four years for each of the VEXAS manifestations – inflammation, cytopenias, clonality, and possible oncogenicity. Special attention is given to contrasting the M41 and non-M41 mutations, aiming to elucidate their differential effects and to identify targetable mechanisms responsible for each of the symptoms. Finally, we explore the therapeutic landscape for VEXAS Syndrome, discussing the efficacy and potential of clone-targeting drugs based on the pathobiology of VEXAS. This includes azacitidine, currently approved for myelodysplastic neoplasms (MDS), novel UBA1 inhibitors being developed for a broad spectrum of cancers, Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) inhibitors, and auranofin, a long-established drug for rheumatoid arthritis. This perspective bridges basic research to clinical symptoms and therapeutics.


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