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Acute myeloid leukemia

Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients

Leukemia volume 31, pages 1069–1078 (2017)Cite this article

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Abstract

The contribution of molecular alterations in bone marrow mesenchymal stromal cells (BM-MSC) to the pathogenesis of acute myeloid leukemia (AML) is poorly understood. Thus we assessed genome-wide genetic, transcriptional and epigenetic alterations in BM-MSC derived from AML patients (AML BM-MSC). Whole-exome sequencing (WES) of AML BM-MSC samples from 21 patients revealed a non-specific pattern of genetic alterations in the stromal compartment. The only mutation present in AML BM-MSC at serial time points of diagnosis, complete remission and relapse was a mutation in the PLEC gene encoding for cytoskeleton key player Plectin in one AML patient. Healthy donor controls did not carry genetic alterations as determined by WES. Transcriptional profiling using RNA sequencing revealed deregulation of proteoglycans and adhesion molecules as well as cytokines in AML BM-MSC. Moreover, KEGG pathway enrichment analysis unravelled deregulated metabolic pathways and endocytosis in both transcriptional and DNA methylation signatures in AML BM-MSC. Taken together, we report molecular alterations in AML BM-MSC suggesting global changes in the AML BM microenvironment. Extended investigations of these altered niche components may contribute to the design of niche-directed therapies in AML.

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Acknowledgements

We gratefully acknowledge funding of the project by Deutsche Krebshilfe as well as German Cancer Translational Consortium (DKTK) and the DKTK joint funding project 'Evaluation of new therapeutic concepts in AML'. Moreover, we thank the High Throughput Sequencing Unit at the DKFZ Genomics and Proteomics Core Facility for providing the Illumina Whole-exome sequencing, whole-genome expression and methylation arrays and related services. Furthermore, we thank Vera Arnemann and colleagues of the Charité Institute of Pathology for helpful assistance with the immunohistochemical stainings.

Author contributions

Conception and design of study: PAG and CDB; patient and donor samples: DN, WKH, CDB; experiments, collection and assembly of data: EKvdH, JOT, KI, CS, ML, LHM, KJ, IA; data analysis and interpretation: EKvdH, MN, SV, ARJ, MPS, PAG, CDB; manuscript writing and editing: EKvdH, MN, LHM, PAG, CDB.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Charité, University Hospital Berlin, Berlin, Germany

    E K von der Heide, M Neumann, A R James, M P Schroeder, J Ortiz-Tanchez, K Isaakidis, C Schlee, M Luther, L H Mochmann & C D Baldus

  2. German Cancer Consortium (DKTK), Heidelberg, Germany

    E K von der Heide, M Neumann, S Vosberg, A R James, M P Schroeder, J Ortiz-Tanchez, K Isaakidis, C Schlee, M Luther, L H Mochmann, P A Greif & C D Baldus

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    E K von der Heide, M Neumann, S Vosberg, A R James, M P Schroeder, J Ortiz-Tanchez, K Isaakidis, C Schlee, M Luther, L H Mochmann, P A Greif & C D Baldus

  4. Department of Internal Medicine III, Experimental Leukemia and Lymphoma Research (ELLF), University Hospital of the Ludwig-Maximilians-Universität (LMU) München, Munich, Germany

    S Vosberg & P A Greif

  5. Institute of Pathology, Charité, University Hospital Berlin, Berlin, Germany

    K Jöhrens & I Anagnostopoulos

  6. Department of Hematology and Oncology, University of Mannheim, Mannheim, Germany

    D Nowak & W K Hofmann

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  1. E K von der Heide
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  2. M Neumann
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Correspondence to C D Baldus.

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von der Heide, E., Neumann, M., Vosberg, S. et al. Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients. Leukemia 31, 1069–1078 (2017). https://doi.org/10.1038/leu.2016.324

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