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Multiple myeloma gammopathies

Genetic and transcriptional landscape of plasma cells in POEMS syndrome

Leukemia volume 33, pages 1723–1735 (2019)Cite this article

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Abstract

POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.

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Acknowledgements

We thank Rika Okada, Miki Takahashi, and Ayumi Koga for their technical assistance; and all clinical staff involved in patient management. This study was supported in part by Grants-in-Aid for Scientific Research of the Japan Society for the Promotion of Science KAKENHI #26461397 and 15K09494 as well as by Grants-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” #25115002 from MEXT, Japan. E.S. was a recipient of JSM Research Award from the Japanese Society of Myeloma.

Author contributions

Y.N., N.M., A.I., S.O., and C.N. conceived and designed the research. Y.N., N.M., Y.I., K.K., C.K.M., N.O.H., S.T., S.S., Y.T., C.O., M.T., T.I., S.Mis., E.S., S.Ku., and C.N. managed care for patients, collected BM samples, and analyzed clinical data. Y.N., N.M., J.T., K.Yos., Y.Shiozawa, M.O., K.A., A.S., S.Ko., O.R., Y.H., D.N., Y.I., and K.K. performed experiments and statistical analyses. Y.Shiraishi, K.C., H.T., and S.Miyano developed the study methodology. Y.N., N.M., J.T., K.Yos., M.O., O.O., K.Yok., M.S., A.I., S.O., and C.N. interpreted data. Y.N. and N.M. actively wrote the manuscript. All authors reviewed the manuscript and approved the final version for submission.

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  1. These authors contributed equally: Yuhei Nagao, Naoya Mimura, June Takeda

Authors and Affiliations

  1. Department of Hematology, Chiba University Hospital, Chiba, Japan

    Yuhei Nagao, Naoya Mimura, Yusuke Isshiki, Kensuke Kayamori, Chika Kawajiri-Manako, Nagisa Oshima-Hasegawa, Shokichi Tsukamoto, Shio Mitsukawa, Yusuke Takeda, Chikako Ohwada, Masahiro Takeuchi, Tohru Iseki, Emiko Sakaida & Chiaki Nakaseko

  2. Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

    Yuhei Nagao & Koutaro Yokote

  3. Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan

    Naoya Mimura, Shio Mitsukawa & Tohru Iseki

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    June Takeda, Kenichi Yoshida & Seishi Ogawa

  5. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yusuke Shiozawa

  6. Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

    Motohiko Oshima, Kazumasa Aoyama, Atsunori Saraya, Shuhei Koide, Ola Rizq, Yusuke Isshiki, Kensuke Kayamori & Atsushi Iwama

  7. Department of Research and Development, Kazusa DNA Research Institute, Kisarazu, Japan

    Yoshinori Hasegawa

  8. Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Dai Nishijima & Satoru Miyano

  9. Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Masashi Sanada

  10. Department of Neurology, Chiba University Graduate School of Medicine, Chiba, Japan

    Sonoko Misawa & Satoshi Kuwabara

  11. Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

  12. Department of Hematology, School of Medicine, International University of Health and Welfare, Narita, Japan

    Chiaki Nakaseko

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  1. Yuhei Nagao
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Correspondence to Naoya Mimura, Seishi Ogawa or Chiaki Nakaseko.

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Nagao, Y., Mimura, N., Takeda, J. et al. Genetic and transcriptional landscape of plasma cells in POEMS syndrome. Leukemia 33, 1723–1735 (2019). https://doi.org/10.1038/s41375-018-0348-x

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