Spectrum of clonal hematopoiesis in VEXAS syndrome

Abstract

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation 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 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred 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), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in 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.

VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management

“…Additional clonal hematopoietic mutations, most commonly DNMT3A and TET2 , have been reported in a large French cohort with frequencies of observance near 25% of patients with VEXAS 16 . In our experience, additional somatic mutations nears 50% and the presence of either DNMT3A or TET2 is associated with increased risk of mortality 45 . The DNMT3A mutations tend to occur with higher variant allele fractions in comparison to TET2 mutations and even in patients with a diagnosis of MDS, the somatic mosaic landscape usually does not align with what is classically seen in MDS.…”

“…Cytogenic analysis of bone marrow cells has shown normal karyotype in the majority (80%) of patients with VEXAS and no cases of complex karyotypes have been reported 45 . Cytogenic aberrations, when present have included del(7q), del(11q), del(13q), del(20q), and ‐Y 45 .…”

“…Cytogenic analysis of bone marrow cells has shown normal karyotype in the majority (80%) of patients with VEXAS and no cases of complex karyotypes have been reported 45 . Cytogenic aberrations, when present have included del(7q), del(11q), del(13q), del(20q), and ‐Y 45 . Additional clonal hematopoietic mutations, most commonly DNMT3A and TET2 , have been reported in a large French cohort with frequencies of observance near 25% of patients with VEXAS 16 .…”

“…While the presence of DNMT3A and TET2 mutations have been associated with increased mortality, the exact mechanisms for the increase in mortality remain unknown and is not due to a higher rate of myeloid clonal transformation. In addition, these mutations in epigenetic regulator genes are associated with epigenetic age acceleration in VEXAS, resulting in biological aging 45 . Clonal growth patterns and hierarchical structures depend on the temporal association with UBA1 mutations 45 .…”

VEXAS‐Syndrom, eine neu beschriebene autoinflammatorische Systemerkrankung mit dermatologischen Manifestationen

“…Jüngst wurden weitere pathogene, somatische Mutationen im UBA1 ‐Gen beschrieben, unter anderem c.167C>T im Kodon 56, c.1861A > T im Kodon 621 sowie Splice‐Varianten (c.118‐1G > C und c.118‐2A > G), 4,8,9,10 deren funktionelle Auswirkungen noch nicht vollumfänglich verstanden sind. Individuen mit UBA1 ‐Mutation zeigen zudem mitunter weitere Mutationen, beispielsweise in den DNMT3A ‐ und TET2 ‐Genen 11,12 …”