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Spectrum of clonal hematopoiesis in VEXAS syndrome

Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna Fernandez, Terra Lasho, Ruba Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy Finke, Matthew J Koster, Abhishek Mangaonkar, Kenneth J Warrington, Kebede Begna, Zhuoer Xie, Amanda K Ombrello, David Viswanatha, Marcela Ferrada, Lorena Wilson, Ronald Go, Taxiarchis Kourelis, Kaaren Reichard, Horatiu Olteanu, Ivana Darden, Dalton Hironaka, Lemlem Alemu, Sachiko Kajigaya, Sofia Rosenzweig, Rodrigo T Calado, Emma M Groarke, Daniel L Kastner, Katherine R Calvo, Colin O Wu, Peter C Grayson, Neal S Young, David B Beck, Bhavisha A Patel, Mrinal M Patnaik
Blood Jul 2023

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.




Institution Type


Indication / Modality

Other, Myelodysplastic Syndrome (MDS)

Goal of Study

CHIP, Clinical Profiling

PAD Project


Analytes Assessed

Extracellular Protein, InDels, SNV



Proof Point Demonstrated

Co-occurrence, Clonality, Multi-omics