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Myelodysplastic syndrome

Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia

Leukemia volume 33, pages 2466–2480 (2019)Cite this article

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Abstract

Islands of CD123high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123+ mononucleated cells that are lineage-negative, CD45+, CD11c−, CD33−, HLA-DR+, BDCA-2+, BDCA-4+ in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34+ cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

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Acknowledgements

This work was supported by grants from the Ligue Nationale Contre le Cancer (Equipe Labellisée), the National Cancer Institute (INCa PL-BIO and PRT-K calls), the Molecular Medicine in Oncology program supported by the Agence Nationale de la Recherche, and the SIRIC SOCRATE program. NL was supported by a grant from the Ligue Nationale Contre le Cancer, MD by the ITMO Cancer (Plan cancer 2014–2019). Part of high-throughput sequencing was performed by the genomic platform of the Institut Curie, which is supported by grants ANR-10-EQPX-03 and ANR10-INBS-09-08 from the Agence Nationale de la Recherche (Investissements d’Avenir) and by Cancéropole Ile de France. We are grateful to Sylvain Baulande and Patricia Legoix-Ne from the genomic platform of Curie Institute and Karine Bailly from the Cochin Institute cytometry and immunobiology facility for their technical support, and to Abdelkrim Achibet from the orthopedic surgery department from the hospital of Le Mans for providing us with bone marrow controls.

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Authors and Affiliations

  1. INSERM U1170, Gustave Roussy Cancer Center, Villejuif, France

    Nolwenn Lucas, Matthieu Duchmann, M’boyba Khadija Diop, Christophe Willekens, Vincent Ribrag, Nathalie Droin & Eric Solary

  2. Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France

    Nolwenn Lucas & Eric Solary

  3. Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France

    Nolwenn Lucas, Véronique Saada, Christophe Willekens, Vincent Ribrag & Eric Solary

  4. INSERM US23, CNRS UMS3655 Gustave Roussy Cancer Center, Villejuif, France

    Philippe Rameau, Gérard Pierron, M’boyba Khadija Diop & Nathalie Droin

  5. INSERM U932, Institut Curie, PSL Research University, Paris, France

    Floriane Noël, Paula Michea & Vassili Soumelis

  6. Inserm U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris, France

    Olivier Kosmider & Michaela Fontenay

  7. Hôpital Cochin, Service d’hématologie biologique, Paris, France

    Olivier Kosmider & Michaela Fontenay

  8. Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    Martin E Fernandez-Zapico, Matthew T. Howard & Rebecca L. King

  9. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA

    Martin E Fernandez-Zapico, Matthew T. Howard & Rebecca L. King

  10. Malignant Hematology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Sandrine Niyongere & Eric Padron

  11. Department of Hematology, Hopital Saint Louis, Universite Paris Diderot, Paris, France

    Pierre Fenaux & Raphael Itzykson

  12. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Mrinal M Patnaik

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  1. Nolwenn Lucas
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  2. Matthieu Duchmann
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Contributions

NL and MD collected the samples and performed the experiments, PR set up and performed flow analyses, FN and PM analyzed the RNA sequencing data, VS and OK performed conventional microscopy, GP the electron microcopy analysis, MEFZ, MTH and RLK the immunohistochemistry, SN and EP measured FLT3L in bone marrow plasma, MKD analyzed the whole-exome sequencing data, PF, RI, CW, VR and MF provided patient samples, ND supervised the genomic analyses, MD performed the statistical analyses, ES wrote the manuscript, MF, VS and MMP corrected the manuscript, MMP and ES supervised the whole project.

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Correspondence to Mrinal M Patnaik or Eric Solary.

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Lucas, N., Duchmann, M., Rameau, P. et al. Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia. Leukemia 33, 2466–2480 (2019). https://doi.org/10.1038/s41375-019-0447-3

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