Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.
Sirenko M., Bernard E., Creignou M., Domenico D., Farina A., Arango Ossa JE., Kosmider O., Hasserjian R., Jädersten M., Germing U., Sanz G., van de Loosdrecht AA., Gurnari C., Follo MY., Thol F., Zamora L., Pinheiro RF., Pellagatti A., Elias HK., Haase D., Sander B., Orna E., Zoldan K., Eder LN., Sperr WR., Thalhammer R., Ganster C., Adès L., Tobiasson M., Palomo L., Della Porta MG., Huberman K., Fenaux P., Belickova M., Savona MR., Klimek VM., Santos FPS., Boultwood J., Kotsianidis I., Santini V., Solé F., Platzbecker U., Heuser M., Valent P., Finelli C., Voso MT., Shih L-Y., Ogawa S., Fontenay M., Jansen JH., Cervera J., Ebert BL., Bejar R., Greenberg PL., Gattermann N., Malcovati L., Cazzola M., Beck DB., Hellström-Lindberg E., Papaemmanuil E.
Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS.