Study Identifies Distinct Subtype of Myelodysplastic Syndromes

Patients with UBA1 mutations may represent a distinct subtype of myelodysplastic syndrome (MDS), according to an abstract presented by Maria Sirenko, PhD, of Memorial Sloan Kettering Cancer Center in New York, at the 65th American Society of Hematology Annual Meeting & Exposition.

Dr. Sirenko and colleagues used targeted next-generation sequencing of the full UBA1 locus to profile diagnostic and treatment-naïve samples from patients with MDS from the International Working Group for MDS cohort. That locus was chosen because of its association with VEXAS; approximately 40% of patients with VEXAS are also diagnosed with MDS.

The researchers identified 35 UBA1 mutations in 34 patients, including 20 who had likely pathogenic variants and 14 who had variants of unknown significance.

Integration of that patient cohort with another cohort yielded 40 patients with pathogenic UBA1 variants. There was a median of one additional myeloid gene mutation in addition to UBA1, most commonly TET2, ASXL1, SF3B1, and loss of the Y chromosome. There was enrichment for UBA1 in male patients with few or no mutations in driver genes (7%).

The majority of patients (73%) with UBA1 variants were considered Molecular International Prognostic Scoring System (IPSS-M) very low/low risk. However, the researchers noted that patients with variants of unknown significance were more likely to be IPSS-M moderate or high risk.

Three of the patients had disease that transformed into acute myeloid leukemia. One of them had a low variant allele function UAB1 p.M41V and TET2, SF3B1, FLT3, and ASXL2 co-mutations at baseline. The second patient had UBA1 p.S56F and a chromosome 7q deletion. The third patient had variant of unknown significance UBA1 p.R869L and IRF1, NFE2, and RRAS co-mutations.

“UBA1 mutations may define a distinct subset of MDS, and its recognition in future guidelines will improve the management of patients with MDS/VEXAS overlap,” the researchers concluded.

Reference

Sirenko M, Bernard E, Creignou M, et al. UBA1 mutations identify a rare but distinct subtype of myelodysplastic syndromes. Abstract #1862. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.