TY - JOUR
T1 - Spectrum of clonal hematopoiesis in VEXAS syndrome
AU - Gutierrez-Rodrigues, Fernanda
AU - Kusne, Yael
AU - Fernandez, Jenna
AU - Lasho, Terra
AU - Shalhoub, Ruba
AU - Ma, Xiaoyang
AU - Alessi, Hugh
AU - Finke, Christy
AU - Koster, Matthew J.
AU - Mangaonkar, Abhishek
AU - Warrington, Kenneth J.
AU - Begna, Kebede
AU - Xie, Zhuoer
AU - Ombrello, Amanda K.
AU - Viswanatha, David
AU - Ferrada, Marcela
AU - Wilson, Lorena
AU - Go, Ronald
AU - Kourelis, Taxiarchis
AU - Reichard, Kaaren
AU - Olteanu, Horatiu
AU - Darden, Ivana
AU - Hironaka, Dalton
AU - Alemu, Lemlem
AU - Kajigaya, Sachiko
AU - Rosenzweig, Sofia
AU - Calado, Rodrigo T.
AU - Groarke, Emma M.
AU - Kastner, Daniel L.
AU - Calvo, Katherine R.
AU - Wu, Colin O.
AU - Grayson, Peter C.
AU - Young, Neal S.
AU - Beck, David B.
AU - Patel, Bhavisha A.
AU - Patnaik, Mrinal M.
N1 - Publisher Copyright:
© 2023
PY - 2023/7/20
Y1 - 2023/7/20
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2022018774
DO - 10.1182/blood.2022018774
M3 - Article
C2 - 37084382
AN - SCOPUS:85164345353
SN - 0006-4971
VL - 142
SP - 244
EP - 259
JO - Blood
JF - Blood
IS - 3
ER -