Spectrum of clonal hematopoiesis in VEXAS syndrome

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

• Tipo de documento: Artigo Científico
• Fonte: Blood; v. 142, n. 3, p. 16-pg., 2023-07-20.

Resumo

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1(mut)) 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. UBA1(mut) were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1(mut) 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), UBA1(mut) 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 UBA1(mut) selection in a clone (pattern 1) or occurring as an UBA1(mut) 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, UBA1(mut) 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. (AU)

• Processo FAPESP: 16/12799-1 - Correlação entre genótipo, comprimento telomérico e fenótipo nas telomeropatias
• Beneficiário: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs