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Myelodysplastic syndrome

Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease

Leukemia volume 35, pages 2720–2724 (2021)Cite this article

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Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid malignancies, characterized by bone marrow failure and a high propensity to evolve to acute myeloid leukemia [1]. They generally display genetic somatic mutations in epigenetic, RNA splicing, transcription, or signaling pathways [1]. Around 25% of MDS/CMML are associated with systemic inflammatory and autoimmune diseases (SIAD) [2], but the underlying pathogenesis mechanisms remain largely unknown [3], while data on mutations observed in patients with both MDS/CMML and SIAD are very scarce [4]. The close relationship between MDS/CMML and SIAD is further strengthened by the positive effect of hypomethylating agents (HMA) frequently observed on SIAD manifestations in those MDS/CMML patients [5]. We thus conducted a retrospective single center study to investigate the mutational and immunological landscape of MDS/CMML associated with SIAD.

From January 2012 to December 2017, 404 patients with MDS/CMML diagnosis based on WHO criteria [6] had next-generation sequencing (NGS) analysis targeting a panel of 80 genes were included (Table S1). Among them, 85 patients presented SIAD, whose diagnosis relied on international criteria and classified as previously described [2], and were compared to a control cohort of 319 MDS/CMML patients without SIAD. MDS/CMML prognosis was assessed using Revised International Prognostic Scoring System [7], while overall survival (OS) and progression-free survival (PFS) were based on International Working Group 2006 criteria [8]. Samples from 28 patients from our whole cohort (Table S2) were collected to analyze CD4+, CD8+ conventional T lymphocytes and CD4+CD25highCD127low regulatory T cells (Treg) phenotype, their activation status and the expression of immune-checkpoint receptors (ICR) (Table S3). The study was conducted in accordance with Helsinki’s declaration.

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Fig. 1: Clinical and molecular comparison between SIAD and control cohorts.
Fig. 2: T-cell cytometry analysis and correlation between the genotype and the immunological landscape.

References

  1. Adès L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014;383:2239–52.

    Article  Google Scholar 

  2. Mekinian A, Grignano E, Braun T, Decaux O, Liozon E, Costedoat-Chalumeau N, et al. Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study. Rheumatology. 2016;55:291–300.

    Article  CAS  Google Scholar 

  3. Braun T, Fenaux P. Myelodysplastic syndromes (MDS) and autoimmune disorders (AD): cause or consequence? Best Pract Res Clin Haematol. 2013;26:327–36.

    Article  CAS  Google Scholar 

  4. Oh Y-J, Shin D-Y, Hwang SM, Kim S-M, Im K, Park HS, et al. Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome. Korean J Intern Med. 2020;35:457–64.

    Article  CAS  Google Scholar 

  5. Fraison J-B, Mekinian A, Grignano E, Kahn J-E, Arlet J-B, Decaux O, et al. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res. 2016;43:13–7.

    Article  CAS  Google Scholar 

  6. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  7. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

    Article  CAS  Google Scholar 

  8. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25.

    Article  CAS  Google Scholar 

  9. Inoue S, Lemonnier F, Mak TW. Roles of IDH1/2 and TET2 mutations in myeloid disorders. Int J Hematol. 2016;103:627–33.

    Article  CAS  Google Scholar 

  10. Bruggner RV, Bodenmiller B, Dill DL, Tibshirani RJ, Nolan GP. Automated identification of stratifying signatures in cellular subpopulations. Proc Natl Acad Sci USA. 2014;111:E2770–7.

    Article  CAS  Google Scholar 

  11. Yue X, Trifari S, Äijö T, Tsagaratou A, Pastor WA, Zepeda-Martínez JA, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016;213:377–97.

    Article  CAS  Google Scholar 

  12. Kordasti SY, Afzali B, Lim Z, Ingram W, Hayden J, Barber L, et al. IL-17-producing CD4+ T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. Br J Haematol. 2009;145:64–72.

    Article  CAS  Google Scholar 

  13. Sallman DA, List A. The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes. Blood. 2019;133:1039–48.

    Article  CAS  Google Scholar 

  14. Ricard L, Hirsch P, Largeaud L, Deswarte C, Jachiet V, Mohty M, et al. Clonal haematopoiesis is increased in early onset in systemic sclerosis. Rheumatology. 2020;59:3499–504.

    Article  CAS  Google Scholar 

  15. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147–52.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the French Ministry of Health and the French National Cancer Institute (#PRT-K 2017-109). It was also supported by research grants from the Association Laurette Fugain (#ALF 2016-07), the Association Force Hémato (Call for projects 2017), the Association pour la Recherche en Immunologie Médicale et Expérimentale (ARIME), and the Association Saint-Louis. The authors also thank Niclas Setterblad, Antonio Alberdi, Marc Delord, Sophie Duchez, and the Technological Platform of the IRSL for their support. The “EMiLy” U1160 INSERM unit is a member of the OPALE Carnot institute.

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Author notes

  1. These authors contributed equally: Nicolas Dulphy, Lionel Adès

Authors and Affiliations

  1. Université de Paris, Department of Hematology, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France

    Lin-Pierre Zhao, Marie Sébert, Raphaël Itzykson, Pierre Fenaux & Lionel Adès

  2. Université de Paris, Institut de Recherche Saint-Louis, EMiLy, INSERM U1160, Paris, France

    Lin-Pierre Zhao, Maxime Boy, Célia Azoulay, Ludivine Amable, Jihene Klibi, Kamel Benlagha, Marion Espéli, Karl Balabanian, Antoine Toubert & Nicolas Dulphy

  3. CNRS, GDR3697 “Microenvironment of tumor niches – Micronit”, Paris, France

    Lin-Pierre Zhao, Maxime Boy, Marion Espéli, Karl Balabanian, Antoine Toubert & Nicolas Dulphy

  4. Université de Paris, Laboratory of Hematology, AP-HP, Hôpital Saint-Louis, Paris, France

    Emmanuelle Clappier

  5. Université de Paris, Institut de Recherche Saint-Louis, INSERM U944, Paris, France

    Marie Sébert, Lina Benajiba, Pierre Fenaux & Lionel Adès

  6. Laboratory of Hematology, Centre Hospitalier Universitaire Lille, Lille, France

    Claude Preudhomme & Alice Marceau-Renaut

  7. INSERM Lille, University of Lille, Lille, France

    Claude Preudhomme & Alice Marceau-Renaut

  8. Université de Paris, Clinical Investigations Center, Hôpital Saint-Louis, AP-HP, Paris, France

    Lina Benajiba

  9. Université de Paris, INSERM/Centre National de la Recherche Scientifique, Unité Mixte de Recherche 944/7212, Paris Cancer Research Institute, Paris, France

    Raphaël Itzykson

  10. Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Saint-Antoine, AP-HP, Paris, France

    Arsène Mekinian & Olivier Fain

  11. Laboratoire d’Immunologie et d’Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France

    Antoine Toubert & Nicolas Dulphy

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  1. Lin-Pierre Zhao
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Contributions

LPZ analyzed the clinical data. MB performed experiments, analyzed biological results, and made figures. CA, LA, and JK performed experiments. EC, MS, CP, AMR, and RI provided clinical information. KB analyzed data. ME, KB, AT, AM, OF, and PF provided scientific expertise. ND designed biological experiments and analyzed data. LA designed the study and wrote the manuscript with LPZ and ND. All authors critically reviewed the manuscript and gave final approval for submission.

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Correspondence to Lionel Adès.

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Zhao, LP., Boy, M., Azoulay, C. et al. Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease. Leukemia 35, 2720–2724 (2021). https://doi.org/10.1038/s41375-021-01152-1

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