Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes
Por:
Sirenko, M, Bernard, E, Creignou, M, Domenico, D, Farina, A, Ossa, JEA, 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, Solè, F, Platzbecker, U, Heuser, M, Valent, P, Finelli, C, Voso, MT, Shih, LY, 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 and Papaemmanuil, E
Publicada:
12 sep 2024
Ahead of Print:
1 sep 2024
Resumen:
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.
Filiaciones:
Sirenko, M:
Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY USA
New York Univ, Dept Pathol, Grossman Sch Med, New York, NY USA
Bernard, E:
Mem Sloan Kettering Canc Ctr, Computat Oncol Serv, Dept Epidemiol & Biostat, New York, NY 10065 USA
Creignou, M:
Karolinska Univ Hosp, Phase Unit 1, Ctr Clin Canc Studies, Stockholm, Sweden
Domenico, D:
Mem Sloan Kettering Canc Ctr, Computat Oncol Serv, Dept Epidemiol & Biostat, New York, NY 10065 USA
Farina, A:
Mem Sloan Kettering Canc Ctr, Integrated Genom Operat, New York, NY USA
Ossa, JEA:
Mem Sloan Kettering Canc Ctr, Computat Oncol Serv, Dept Epidemiol & Biostat, New York, NY 10065 USA
Kosmider, O:
Univ Paris Cite, Inst Cochin, Paris, France
Ctr Univ Paris Cite, Cochin Hosp, Hematol Lab, Assistance Publ Hop Paris, Paris, France
Hasserjian, R:
Harvard Med Sch, Dept Pathol, Boston, MA USA
Jädersten, M:
Karolinska Univ Hosp, Dept Med Huddinge, Ctr Hematol & Regenerat Med, Stockholm, Sweden
Germing, U:
Univ Klin Dusseldorf, Dept Hematol Oncol & Clin Immunol, Dusseldorf, Germany
Sanz, G:
Hlth Res Inst La Fe, Hosp Univ & Politecn La Fe, Dept Hematol, Valencia, Spain
van de Loosdrecht, AA:
Vrije Univ, Amsterdam Univ, Dept Hematol, Med Ctr, Amsterdam, Netherlands
Gurnari, C:
Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH USA
Follo, MY:
Univ Bologna, Cell Signalling Lab, Dept Biomed & Neuromotor Sci, Bologna, Italy
Thol, F:
Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany
:
Univ Autonoma Barcelona, Inst Catala Oncol Hosp Univ Germans Trias i Pujol, Josep Carreras Leukaemia Res Inst, Dept Hematol, Badalona, Spain
Pinheiro, RF:
Univ Fed Ceara, Dept Clin Med, Fortaleza, Brazil
Pellagatti, A:
Univ Oxford, Dept Med, Radcliffe Dept Med, Oxford BRC Haematol Theme, Oxford, England
Elias, HK:
Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA
Haase, D:
Georg August Univ, Univ Med Ctr Gottingen, Clin Hematol & Med Oncol, Gottingen, Germany
Sander, B:
Karolinska Inst, Dept Lab Med, Stockholm, Sweden
Karolinska Univ Hosp, Dept Pathol & Canc Diagnost, Stockholm, Sweden
:
Univ Autonoma Barcelona, Inst Catala Oncol Hosp Univ Germans Trias i Pujol, Josep Carreras Leukaemia Res Inst, Dept Hematol, Badalona, Spain
Zoldan, K:
Univ Med Ctr Leipzig, Dept Med Hematol Cellular Therapy Hemostaseol & I, Leipzig, Germany
Eder, LN:
Georg August Univ, Univ Med Ctr Gottingen, Clin Hematol & Med Oncol, Gottingen, Germany
Sperr, WR:
Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria
Med Univ Vienna, Ludwig Boltzmann Inst Hematol & Oncol, Vienna, Austria
Med Univ Vienna, Dept Lab Med, Vienna, Austria
Ganster, C:
Univ Med Ctr, INDIGHO Labs, Clin Hematol & Med Oncol, Gottingen, Germany
Adès, L:
Univ Paris, Hop St Louis, Assistance Publ Hop Paris, Dept Hematol, Paris, France
Tobiasson, M:
Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden
:
Vall dHebron Inst Oncol, Expt Hematol Unit, Barcelona, Spain
Della Porta, MG:
Humanitas Res Hosp, Canc Ctr, Milan, Italy
Humanitas Univ, Milan, Italy
Huberman, K:
Mem Sloan Kettering Canc Ctr, Integrated Genom Operat, New York, NY USA
Fenaux, P:
Univ Paris, St Louis Hosp, Dept Hematol, Paris, France
Belickova, M:
Inst Hematol & Blood Transfus, Dept Genom, Prague, Czech Republic
Savona, MR:
Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Med Ctr, Nashville, TN USA
Klimek, VM:
Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY USA
Santos, FPS:
Hosp Israelita Albert Einstein, Oncol Hematol Ctr, Sao Paulo, Brazil
Boultwood, J:
Univ Oxford, John Radcliffe Hosp, Nuffield Div, Bloodwise Mol Haematol Unit,Clin Lab Sci, Oxford, England
Kotsianidis, I:
Democritus Univ Thrace, Sch Med, Dept Hematol, Alexandroupolis, Greece
Santini, V:
Univ Florence, Azienda Osped Univ Careggi, Dept Expt & Clin Med, Myelodysplast Syndromes Unit, Florence, Italy
Solè, F:
Josep Carreras Leukaemia Res Inst, Myelodysplast Syndromes Res Grp, Badalona, Spain
Platzbecker, U:
Univ Leipzig, Med Clin & Policlin Hematol & Cellular Therapy 1, Med Ctr, Leipzig, Germany
Heuser, M:
Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany
Valent, P:
Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria
Med Univ Vienna, Ludwig Boltzmann Inst Hematol & Oncol, Vienna, Austria
Med Univ Vienna, Dept Lab Med, Vienna, Austria
Finelli, C:
IRCCS Azienda Osped Univ Bologna, Inst Hematol Seragnoli, Bologna, Italy
Voso, MT:
Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy
Shih, LY:
Chang Gung Mem Hosp, Div Hematol Oncol, Taoyuan, Taiwan
Chang Gung Univ, Taoyuan, Taiwan
Ogawa, S:
Kyoto Univ, Dept Pathol & Tumor Biol, Grad Sch Med, Kyoto, Japan
Fontenay, M:
Univ Paris Cite, Inst Cochin, Paris, France
Ctr Univ Paris Cite, Cochin Hosp, Hematol Lab, Assistance Publ Hop Paris, Paris, France
Jansen, JH:
Radboud Univ Nijmegen, Dept Lab Med, Hematol Lab, Med Ctr, Nijmegen, Netherlands
Cervera, J:
Univ Hosp La Fe, Dept Hematol & Genet Unit, Valencia, Spain
Ebert, BL:
Howard Hughes Med Inst, Boston, MA USA
Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA
Bejar, R:
Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA
Greenberg, PL:
Stanford Univ, Hematol Div, Dept Med, Stanford Canc Ctr, Stanford, CA USA
Gattermann, N:
Heinrich Heine Univ, Dept Hematol Oncol & Clin Immunol, Dusseldorf, Germany
Malcovati, L:
Univ Pavia, Dept Mol Med, Pavia, Italy
Univ Pavia, Fdn Ist Ricovero & Cura Carattere Sci Policlin Sa, Pavia, Italy
Beck, DB:
NYU Grossman Sch Med, Dept Med, Div Rheumatol, New York, NY USA
Hellström-Lindberg, E:
Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden
Papaemmanuil, E:
Mem Sloan Kettering Canc Ctr, Computat Oncol Serv, Dept Epidemiol & Biostat, New York, NY 10065 USA
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