. 2024 Sep 12;144(11):1221-1229.

doi: 10.1182/blood.2023023723.

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Maria Sirenko^{1

2

3}, Elsa Bernard², Maria Creignou⁴, Dylan Domenico², Andrea Farina⁵, Juan E Arango Ossa², Olivier Kosmider^{6

7}, Robert Hasserjian⁸, Martin Jädersten⁹, Ulrich Germing¹⁰, Guillermo Sanz¹¹, Arjan A van de Loosdrecht¹², Carmelo Gurnari¹³, Matilde Yung Follo¹⁴, Felicitas Thol¹⁵, Lurdes Zamora¹⁶, Ronald Feitosa Pinheiro¹⁷, Andrea Pellagatti¹⁸, Harold K Elias¹⁹, Detlef Haase²⁰, Birgitta Sander^{21

22}, Elisa Orna¹⁶, Katharina Zoldan²³, Lea Naomi Eder²⁰, Wolfgang R Sperr^{24

25}, Renate Thalhammer²⁶, Christina Ganster²⁷, Lionel Adès²⁸, Magnus Tobiasson²⁹, Laura Palomo³⁰, Matteo Giovanni Della Porta³¹, Kety Huberman⁵, Pierre Fenaux³², Monika Belickova³³, Michael R Savona³⁴, Virginia M Klimek³⁵, Fabio P S Santos³⁶, Jacqueline Boultwood³⁷, Ioannis Kotsianidis³⁸, Valeria Santini³⁹, Francesc Solé⁴⁰, Uwe Platzbecker⁴¹, Michael Heuser¹⁵, Peter Valent^{24

25}, Carlo Finelli⁴², Maria Teresa Voso⁴³, Lee-Yung Shih⁴⁴, Seishi Ogawa⁴⁵, Michaela Fontenay^{6

7}, Joop H Jansen⁴⁶, Jose Cervera⁴⁷, Benjamin L Ebert^{48

49}, Rafael Bejar⁵⁰, Peter L Greenberg⁵¹, Norbert Gattermann⁵², Luca Malcovati⁵³, Mario Cazzola⁵⁴, David B Beck⁵⁵, Eva Hellström-Lindberg²⁹, Elli Papaemmanuil²

Affiliations

¹ Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY.
² Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
³ Department of Pathology, New York University Grossman School of Medicine, New York, NY.
⁴ Phase 1 Unit, Center for Clinical Cancer Studies, Karolinska University Hospital, Stockholm, Sweden.
⁵ Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY.
⁶ Institut Cochin, Université de Paris Cité, Paris, France.
⁷ Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital, Paris, France.
⁸ Department of Pathology, Harvard Medical School, Boston, MA.
⁹ Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Hematology, Oncology and Clinical Immunology, Universitatsklinik Dusseldorf, Dusseldorf, Germany.
¹¹ Department of Hematology, Hospital Universitario y Politécnico La Fe, Health Research Institute La Fe, Valencia, Spain.
¹² Department of Hematology, Amsterdam University Medical Center, Vrije University Medical Center, Amsterdam, The Netherlands.
¹³ Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
¹⁴ Department of Biomedical and Neuromotor Sciences, Cell Signalling Laboratory, University of Bologna, Bologna, Italy.
¹⁵ Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
¹⁶ Hematology Department, Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
¹⁷ Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil.
¹⁸ Radcliffe Department of Medicine, Oxford BRC Haematology Theme, University of Oxford, Oxford, United Kingdom.
¹⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
²⁰ Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.
²¹ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
²² Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
²³ Department of Medicine 1, Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany.
²⁴ Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
²⁵ Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
²⁶ Department of Laboratory Medicine, Medical University of Vienna, Austria.
²⁷ Clinics of Hematology and Medical Oncology, INDIGHO Laboratories, University Medical Center, Göttingen, Germany.
²⁸ Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.
²⁹ Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁰ Experimental Hematology Unit, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
³¹ Cancer Center, Humanitas Research Hospital and Humanitas University, Milan, Italy.
³² Department of Hematology, Université de Paris, Saint-Louis Hospital, Paris, France.
³³ Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
³⁴ Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.
³⁵ Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁶ Oncology-Hematology Center, Hospital Israelita Albert Einstein, São Paulo, Brazil.
³⁷ Nuffield Division of Clinical Laboratory Sciences, Bloodwise Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
³⁸ Department of Hematology, Democritus Thrace University, School of Medicine, Alexandroupolis, Greece.
³⁹ Myelodysplastic Syndromes Unit, Department of Experimental and Clinical Medicine, Hematology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.
⁴⁰ Myelodysplastic Syndromes Research Group, Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Spain.
⁴¹ Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Leipzig Medical Center, Leipzig, Germany.
⁴² Institute of Hematology "Sèragnoli," IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁴³ Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
⁴⁴ Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
⁴⁵ Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁶ Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁷ Department of Hematology and Genetics Unit, University Hospital La Fe, Valencia, Spain.
⁴⁸ Howard Hughes Medical Institute, Boston, MA.
⁴⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
⁵⁰ Moores Cancer Center at University of California San Diego, La Jolla, CA.
⁵¹ Hematology Division, Department of Medicine, Stanford Cancer Center, Stanford University, Stanford, CA.
⁵² Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-Universität, Düsseldorf, Germany.
⁵³ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁵⁴ Fondazione Istituto di Ricovero e Cura Carattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy.
⁵⁵ Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY.

PMID: 38687605
PMCID: PMC12060156
DOI: 10.1182/blood.2023023723

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Maria Sirenko et al. Blood. 2024.

. 2024 Sep 12;144(11):1221-1229.

doi: 10.1182/blood.2023023723.

Authors

Affiliations

¹ Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY.
² Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
³ Department of Pathology, New York University Grossman School of Medicine, New York, NY.
⁴ Phase 1 Unit, Center for Clinical Cancer Studies, Karolinska University Hospital, Stockholm, Sweden.
⁵ Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY.
⁶ Institut Cochin, Université de Paris Cité, Paris, France.
⁷ Hematology Laboratory, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris Cité, Cochin Hospital, Paris, France.
⁸ Department of Pathology, Harvard Medical School, Boston, MA.
⁹ Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Hematology, Oncology and Clinical Immunology, Universitatsklinik Dusseldorf, Dusseldorf, Germany.
¹¹ Department of Hematology, Hospital Universitario y Politécnico La Fe, Health Research Institute La Fe, Valencia, Spain.
¹² Department of Hematology, Amsterdam University Medical Center, Vrije University Medical Center, Amsterdam, The Netherlands.
¹³ Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
¹⁴ Department of Biomedical and Neuromotor Sciences, Cell Signalling Laboratory, University of Bologna, Bologna, Italy.
¹⁵ Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
¹⁶ Hematology Department, Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
¹⁷ Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil.
¹⁸ Radcliffe Department of Medicine, Oxford BRC Haematology Theme, University of Oxford, Oxford, United Kingdom.
¹⁹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
²⁰ Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.
²¹ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
²² Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
²³ Department of Medicine 1, Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany.
²⁴ Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
²⁵ Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
²⁶ Department of Laboratory Medicine, Medical University of Vienna, Austria.
²⁷ Clinics of Hematology and Medical Oncology, INDIGHO Laboratories, University Medical Center, Göttingen, Germany.
²⁸ Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.
²⁹ Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁰ Experimental Hematology Unit, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
³¹ Cancer Center, Humanitas Research Hospital and Humanitas University, Milan, Italy.
³² Department of Hematology, Université de Paris, Saint-Louis Hospital, Paris, France.
³³ Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
³⁴ Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.
³⁵ Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
³⁶ Oncology-Hematology Center, Hospital Israelita Albert Einstein, São Paulo, Brazil.
³⁷ Nuffield Division of Clinical Laboratory Sciences, Bloodwise Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
³⁸ Department of Hematology, Democritus Thrace University, School of Medicine, Alexandroupolis, Greece.
³⁹ Myelodysplastic Syndromes Unit, Department of Experimental and Clinical Medicine, Hematology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.
⁴⁰ Myelodysplastic Syndromes Research Group, Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Spain.
⁴¹ Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Leipzig Medical Center, Leipzig, Germany.
⁴² Institute of Hematology "Sèragnoli," IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁴³ Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
⁴⁴ Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
⁴⁵ Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁶ Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴⁷ Department of Hematology and Genetics Unit, University Hospital La Fe, Valencia, Spain.
⁴⁸ Howard Hughes Medical Institute, Boston, MA.
⁴⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
⁵⁰ Moores Cancer Center at University of California San Diego, La Jolla, CA.
⁵¹ Hematology Division, Department of Medicine, Stanford Cancer Center, Stanford University, Stanford, CA.
⁵² Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-Universität, Düsseldorf, Germany.
⁵³ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁵⁴ Fondazione Istituto di Ricovero e Cura Carattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy.
⁵⁵ Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY.

PMID: 38687605
PMCID: PMC12060156
DOI: 10.1182/blood.2023023723

Abstract

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.

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Conflict of interest statement

Conflict-of-interest disclosure: U.G. has received honoraria from Celgene, Novartis, Amgen, Janssen, Roche, and Jazz; and has received research funding from Celgene and Novartis. A.A.v.d.L. serves on advisory boards of Celgene, Amgen, Roche, Novartis, and Alexion; and has received research funding from Celgene. F.T. serves on the advisory boards of Jazz, Pfizer, and AbbVie; and has received research funding from Celgene. I.K. serves on the advisory board of Genesis Pharma; and has received research funding from Celgene and Janssen Hellas. F.P.S.S. has received honoraria from Janssen-Cilag, Bristol Myers Squibb, Novartis, Amgen, AbbVie, and Pfizer; serves on the advisory boards of Novartis, Amgen, and AbbVie; and has received research funding from Novartis. M.R.S. serves on the advisory boards of AbbVie, Astex, Celgene, Karyopharm, Selvita, and TG Therapeutic; has equity in Karyopharm; and has received research funding from Astex, Incyte, Sunesis, Takeda, and TG Therapeutics. G.S. serves on the advisory boards of AbbVie, Amgen, Astellas, Böehringer-Ingelheim, Celgene, Helsinn Healthcare, Hoffmann-La Roche, Janssen-Cilag, Novartis, and Onconova; and has received research funding from Celgene, Hoffmann-La Roche, Janssen-Cilag, and Novartis. L.A. serves on the advisory boards of AbbVie, Astex, Celgene, and Novartis and has received research funding from Celgene. M.H. has received honoraria from Novartis, Pfizer, and PriME Oncology; serves on the advisory boards of AbbVie, Bayer Pharma, Daiichi Sankyo, Novartis, and Pfizer and has received institutional research funding from Astellas, Bayer Pharma, BergenBio, Daiichi Sankyo, Karyopharm, Novartis, Pfizer, and Roche. P.V. has received honoraria and research funding from Celgene. C.F. serves on the advisory boards of, and has received honoraria from, Celgene, Novartis, and Janssen; and has received research funding from Celgene. M.T.V. serves on the advisory board of Celgene; has received honoraria from Celgene and Novartis; and has received research funding from Celgene. N.G. serves on the advisory board of, and has received honoraria from, Novartis; and has received research funding from Alexion. B.L.E. has received research funding from Celgene and Deerfield. R.B. serves on the advisory boards of Celgene, AbbVie, Astex, NeoGenomics, and Daiichi Sankyo; and has received research funding from Celgene and Takeda. D.B.B. receives consulting fees from Alexion Pharmaceuticals and is on the advisory boards for Novartis and Sobi. E.H.-L. has received research funding from Celgene. E.P. is a founder, equity holder, and holds fiduciary roles in Isabl Inc, a company offering analytics for cancer whole-genome sequencing data; and holds stock options in TenSixteen Bio. The remaining authors declare no competing financial interests.

Figures

**Figure 1.**
**Prevalence of *UBA1* mutations in MDS.** (A) Schematic of study design showing cohort A (top) profiled by ddPCR and cohort B (bottom) profiled by NGS for *UBA1* mutations. (B) Lollipop plot showing likely pathogenic mutations (top) and VUS (bottom) in *UBA1* detected by ddPCR and/or NGS. Variants are colored by VAF and point shape indicates whether the variant was detected by ddPCR, NGS, or both. VUS in the noncanonical transcripts are reported below the x-axis. (C) VAF of *UBA1* mutations detected by NGS in cohort B, adjusted for single copy of chromosome X in males. (D) Correlation of *UBA1* NGS VAF and ddPCR mutant droplet fraction for patients (n = 8) with *UBA1* p.M41T/V/L variants detected by both assays. (E) Stacked bar plot of WHO 2016 classification (available for n = 53/54). (F) Stacked bar plot of IPSS-M risk category (available for n = 48/54). (G) Stacked bar plot of number of co-occurring mutations in 54 patients with *UBA1*-mutated MDS (left) and cohort B (right).

**Figure 2.**
**Comutation patterns and clinical presentation of *UBA1*-mutated MDS.** (A) Oncoprint for the total cohort of patients with *UBA1*-mutant MDS (n = 54) including results of retrospective review of clinical history for inflammatory features (bottom). Patients are ordered by decreasing *UBA1* VAF per group (p.M41, non-p.M41 pathogenic, and VUS). (B) Frequency of comutations in patients with *UBA1*-mutated and –wild-type MDS. (C) VAF of pathogenic *UBA1* and co-occurring *DNMT3A* (left) and *TET2* (right) mutations. *UBA1* VAF was adjusted for single copy of ChrX for comparison with heterozygous mutations in this analysis. Gray dashed line represents the identity line. Black solid line represents a linear model fit to the data. (D) Stacked bar plot of clinical inflammatory manifestations for n = 54 patients. (E) Kaplan-Meier curve for overall survival in cohort A (ddPCR) of patients with MDS with (blue) or without (red) *UBA1* p.M41T/V/L mutations. Number of patients per group and P values are indicated on the plot. APR, acute phase reactants; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase.

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Comment in

Bone marrow vexations.
Fox LC. Fox LC. Blood. 2024 Sep 12;144(11):1140-1141. doi: 10.1182/blood.2024024971. Blood. 2024. PMID: 39264609 No abstract available.

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Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Affiliations

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous