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      Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q)

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          Abstract

          Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.

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          The online version contains supplementary material available at 10.1007/s00277-021-04492-1.

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          Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays.

          The recently released Infinium HumanMethylation450 array (the '450k' array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ∼450 000 loci across a range of genomic features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost-effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years. Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods. http://bioconductor.org/packages/release/bioc/html/minfi.html. khansen@jhsph.edu; rafa@jimmy.harvard.edu Supplementary data are available at Bioinformatics online.
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            Adaptive linear step-up procedures that control the false discovery rate

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              Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

              Summary Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the CRL4CRBN E3 ubiquitin ligase, resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for lenalidomide's therapeutic window in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. These findings have implications for the clinical activity of lenalidomide and related compounds and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.
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                Author and article information

                Contributors
                anna.hecht@medma.uni-heidelberg.de
                Journal
                Ann Hematol
                Ann Hematol
                Annals of Hematology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0939-5555
                1432-0584
                27 April 2021
                27 April 2021
                2021
                : 100
                : 6
                : 1463-1471
                Affiliations
                [1 ]GRID grid.411778.c, ISNI 0000 0001 2162 1728, Department of Hematology and Oncology, , University Hospital Mannheim, ; Mannheim, Germany
                [2 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Pediatrics, , University of California San Francisco, ; San Francisco, CA USA
                [3 ]GRID grid.412282.f, ISNI 0000 0001 1091 2917, Department of Hematology, , University Hospital Dresden, ; Dresden, Germany
                [4 ]GRID grid.459730.c, ISNI 0000 0004 0558 4607, Department of Hematology, Oncology and Palliative Care, , Marien Hospital Duesseldorf, ; Duesseldorf, Germany
                [5 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Internal Medicine, , Technical University of Munich, ; Munich, Germany
                [6 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Department of Hematology and Oncology, Charité, , Benjamin Franklin University, ; Berlin, Germany
                [7 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Clinics of Hematology and Medical Oncology, , University Medicine Goettingen, ; Goettingen, Germany
                [8 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Internal Medicine V, , Heidelberg University Hospital, ; Heidelberg, Germany
                [9 ]GRID grid.420057.4, ISNI 0000 0004 7553 8497, MLL Munich Leukemia Laboratory, ; Munich, Germany
                [10 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Oncology, Hematology, BMT with section Pneumology, Hubertus Wald Cancer Center, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [11 ]GRID grid.411088.4, ISNI 0000 0004 0578 8220, Department of Internal Medicine, , University Hospital Frankfurt, ; Frankfurt, Germany
                [12 ]GRID grid.7708.8, ISNI 0000 0000 9428 7911, Internal Medicine, , University Hospital Freiburg, ; Freiburg, Germany
                [13 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, , Hannover Medical School, ; Hannover, Germany
                [14 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Hannover Medical School, , Institute of Pathology, ; Hannover, Germany
                [15 ]GRID grid.411327.2, ISNI 0000 0001 2176 9917, Department for Hematology, Oncology and Clinical Immunology, University Hospital, , Heinrich-Heine-University, ; Duesseldorf, Germany
                [16 ]Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany
                Article
                4492
                10.1007/s00277-021-04492-1
                8116243
                33903952
                e810069a-7c05-4de9-b492-61655781e51e
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 November 2020
                : 8 March 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: NO817/5-2
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005972, Deutsche Krebshilfe;
                Award ID: 70113953
                Award Recipient :
                Funded by: Gutermuth Foundation
                Funded by: H.W. & J. Hector Fund
                Award ID: M83
                Award Recipient :
                Funded by: Dr. Rolf M. Schwiete Fund
                Award ID: Project 20/2016
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005677, José Carreras Leukämie-Stiftung;
                Award ID: DJCLS H 03/01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006436, Celgene;
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Hematology
                myelodysplastic syndromes,deletion 5q,lenalidomide,dna methylation
                Hematology
                myelodysplastic syndromes, deletion 5q, lenalidomide, dna methylation

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