[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-332544-105":59,"doc-detail-332544-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","uba1-dysfunction-in-vexas-and-cancer","UBA1 dysfunction in VEXAS and cancer","","UBA1 is an X-linked ubiquitin E1 enzyme that initiates a central post-translational modification step. Partial UBA1 loss-of-function mutations in hematopoietic stem and progenitor cells cause VEXAS Syndrome, a hematoinflammatory disorder mainly affecting older males, marked by severe inflammation, cytopenias, and links to hematologic malignancies. This research perspective reviews molecular consequences and recent advances across inflammation, cytopenias, clonality, and potential oncogenicity, contrasting M41 vs non-M41 variants and summarizing therapeutic options including clone-targeting approaches and PERK inhibitors.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/uba1-dysfunction-in-vexas-and-cancer/332544/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/uba1-dysfunction-in-vexas-and-cancer/332544.png","ImageObject",300,407,{"name":92,"@type":93},"Riley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does UBA1 play in the ubiquitin pathway relevant to VEXAS?","Question",{"text":112,"@type":113},"UBA1 encodes a ubiquitin E1 enzyme that initiates ubiquitylation by activating ubiquitin, which is required for downstream ubiquitin transfer to substrates.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do UBA1 mutations lead to VEXAS Syndrome clinical features?",{"text":117,"@type":113},"Somatic UBA1 loss-of-function mutations in hematopoietic stem and progenitor cells drive severe, refractory inflammation and cytopenias, and some patients develop hematologic malignancies.",{"name":119,"@type":110,"acceptedAnswer":120},"What treatment approaches are discussed for VEXAS Syndrome?",{"text":121,"@type":113},"The perspective reviews therapeutic options including azacitidine, clone-targeting drugs and emerging UBA1 inhibitors, as well as PERK inhibitors and auranofin based on the disorder’s underlying pathobiology.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332544,1790115102,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2024, Vol. 15, pp: 644-658  \nResearch Perspective  \nUBA1 dysfunction in VEXAS and cancer  \nMaki Sakuma 1,2, Torsten Haferlach 1 and Wencke Walter 1  \n1 MLL Munich Leukemia Laboratory, Munich, Germany  \n2 Medical Graduate Center, Technical University Munich, Munich, Germany Correspondence to: Wencke Walter, [email](email: wencke.walter@mll.com)[: wencke.walter@mll.com](email: wencke.walter@mll.com)[ ](email: wencke.walter@mll.com)[Keywords](Keywords: VEXAS)[: VEXAS](Keywords: VEXAS); MDS; clonal cytopenia; ubiquitin; inflammation  \nReceived: August 05, 2024 Accepted: August 18, 2024 Published: September 30, 2024  \nCopyright: © 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.  \nABSTRACT  \nUBA1, 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 fora 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.  \nINTRODUCTION  \nThe UBA1 (Ubiquitin-like modifier activating enzyme 1) gene, located on the X chromosome, has recently gathered significant interest within the medical community following the 2020 discovery of VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammation, Somatic) Syndrome [1] . This novel, difficult-to-treat hemato-inflammatory disorder is caused by three somatic mutations in UBA1, a gene encoding for a key E1 enzyme within the ubiquitin proteasome system (UPS) . These mutations, found in hematopoietic stem and progenitor cells predominantly in older males, lead to severe and refractory inflammatory symptoms and loss of mature blood cells (cytopenias). Additionally, a portion of these patients develop hematologic malignancies, including myelodysplastic neoplasms (MDS) and multiple myeloma.  \nNotably, despite the increased risk of acute myeloid leukemia (AML) in MDS patients [2], progression toAML is extremely rare in patients with VEXAS-MDS [3] .  \nVEXAS Syndrome captured the attention of a wideranging audience beyond its initial classification as a rare genetic disease, with only 28 described male patients, partly because the genetic mutation was of somatic origin with a cancer association. The perturbation of the UPS is a long-standing cause of inflammation, evidenced by multiple pediatric monogenic autoinflammatory diseases [4] . However, adult-onset genetic inflammatory diseases were not known. It is indeed surprising that loss of function of UBA1 would lea","cbCaio4CisAVTxq6","https://ap.wps.com/l/cbCaio4CisAVTxq6","pdf",2745719,15,"English","# Introduction\n## UBA1 loss of function and VEXAS\n## UBA1 dysfunction in VEXAS and cancer","[{\"question\":\"What role does UBA1 play in the ubiquitin pathway relevant to VEXAS?\",\"answer\":\"UBA1 encodes a ubiquitin E1 enzyme that initiates ubiquitylation by activating ubiquitin, which is required for downstream ubiquitin transfer to substrates.\"},{\"question\":\"How do UBA1 mutations lead to VEXAS Syndrome clinical features?\",\"answer\":\"Somatic UBA1 loss-of-function mutations in hematopoietic stem and progenitor cells drive severe, refractory inflammation and cytopenias, and some patients develop hematologic malignancies.\"},{\"question\":\"What treatment approaches are discussed for VEXAS Syndrome?\",\"answer\":\"The perspective reviews therapeutic options including azacitidine, clone-targeting drugs and emerging UBA1 inhibitors, as well as PERK inhibitors and auranofin based on the disorder’s underlying pathobiology.\"}]","UBA1 dysfunction in VEXAS and cancer | PDF",1789998650,38]