Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.

Autores de IIS La Fe

• Guillermo Sanz Santillana

  Autor

• José Vicente Cervera Zamora

  Autor

Participantes ajenos a IIS La Fe

• Sirenko, M
• Bernard, E
• Creignou, M
• Domenico, D
• Farina, A
• Arango Ossa, Juan Esteban
• Kosmider, O
• Hasserjian, R
• Jadersten, Martin
• Germing, U
• 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
• Ades, Lionel
• 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
• Solè, F
• Platzbecker, U
• Heuser, M
• Valent, P
• Finelli, C
• Voso, MT
• Shih, LY
• Ogawa, S
• Fontenay, M
• Jansen, JH
• Ebert, BL
• Bejar, R
• Greenberg, PL
• Gattermann, N
• Malcovati, L
• Cazzola, M
• Beck, DB
• Hellstrom-Lindberg, Eva S
• Papaemmanuil, E

Grupos

• Hematología y Hemoterapia

Abstract

Mutations in UBA1, which are disease-defining for VEXAS 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 PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established 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=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one 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 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

Copyright © 2024 American Society of Hematology.

Keywords

• HEALTH-ORGANIZATION CLASSIFICATION; VEXAS SYNDROME; MANIFESTATIONS