Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

Sakuma, M; Blombery, P; Meggendorfer, M; Haferlach, C; Lindauer, M; Martens, UM; Kern, W; Haferlach, T; Walter, W

Author(s): Sakuma, M; Blombery, P; Meggendorfer, M; Haferlach, C; Lindauer, M; Martens, UM; Kern, W; Haferlach, T; Walter, W;
Details: Publication Year 2023-05,Volume 37,Issue #5,Page 1080-1091
Journal Title: Leukemia
Publication Type: Research article
Abstract: UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1(non-M41)) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1(non-M41) putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1(non-M41) putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1(M41) patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1(non-M41) variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.
Publisher: Springer Nature
Keywords: Humans; Male; *Hematologic Neoplasms/genetics; *Neoplasms; Transcriptome; Ubiquitin-Activating Enzymes/genetics
Department(s): Clinical Haematology; Pathology
PubMed ID: 36823397
Publisher's Version: https://doi.org/10.1038/s41375-023-01857-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41375-023-01857-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-05 06:33:27

Last Modified: 2023-09-05 06:34:32