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Myelodysplastic Syndromes
Deep sequencing of bone marrow microenvironments of patients with del(5q) myelodysplastic syndrome reveals imprints of antigenic selection as well as generation of novel T-cell clusters as a response pattern to lenalidomide
Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1355-1364
Thorben Mährle,1* Nuray Akyüz,1* Pim Fuchs,2 Nicola Bonzanni,2 Donjete Simnica,1,3 Ulrich Germing,4 Anne Marie Asemissen,1 Johann Christoph Jann,5 Florian Nolte,5 Wolf-Karsten Hofmann,5 Daniel Nowak5 and Mascha Binder1,3
1Department of Oncology and Hematology, BMT with Pneumology section, Hubertus Wald Tumorzentrum / UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2ENPICOM, ‘s-Hertogenbosch, the Netherlands; 3Department of Hematology and Oncology, University Hospital Halle (Saale), Germany; 4Department of Hematology, Oncology, and Clinical Immunology, Heinrich Heine University Düsseldorf, Germany and 5Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Mannheim, Germany
*TM and NA contributed equally to this work.
ABSTRACT
In myelodysplastic syndromes with a partial deletion of the long arm of chromosome 5, del(5q), lenalidomide is believed to reverse anergic T-cell immunity in the bone marrow resulting in suppression of the del(5q) clone. In this study we used next-generation sequencing of immunoglobu- lin heavy chain (IGH) and T-cell receptor beta (TRB) rearrangements in bone marrow-residing and peripheral blood-circulating lymphocytes of patients with del(5q) myelodysplastic syndromes to assess the immune architecture and track adaptive immune responses during treatment with lenalidomide. The baseline bone marrow B-cell space in patients was comparable to that of age-matched healthy controls in terms of gene usage and IGH clonality, but showed a higher percentage of hypermutated IGH sequences, indicat- ing an expanded number of antigen-experienced B lineage cells. Bone mar- row B lineage clonality decreased significantly and hypermutated IGH clones normalized upon lenalidomide treatment, well in line with the pro- liferative effect on healthy antigen-inexperienced B-cell precursors previ- ously described for this drug. The T-cell space in bone marrow of patients with del(5q) myelodysplastic syndromes showed higher TRB clonality compared to that of healthy controls. Upon lenalidomide treatment, myelodysplastic syndrome-specific T-cell clusters with low to medium spontaneous generation probabilities emerged; these clusters were shared across patients, indicating a common antigen-driven T-cell response pat- tern. Hence, we observed B lineage diversification and generation of new, antigen-dependent T-cell clusters, compatible with a model of adaptive immunity induced against the del(5q) clone by lenalidomide. Overall, this supports the concept that lenalidomide not only alters the functional T-cell state, but also the composition of the T- and B-cell repertoires in del(5q) myelodysplastic syndromes.
Introduction
Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by inefficient hematopoiesis. The most prevalent cytogenetic abnormality in these diseases is a partial deletion of the long arm of chromosome 5, del(5q), which is present in about 15% of patients.1 This clinically distinct entity is char-
Correspondence:
MASCHA BINDER,
mascha.binder@uk-halle.de
Received: October 8, 2018. Accepted: January 15, 2019. Pre-published: January 24, 2019.
doi:10.3324/haematol.2018.208223
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1355
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