Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis
Yusuke Isshiki, Motohiko Oshima, Naoya Mimura, Kensuke Kayamori, Yurie Miyamoto-Nagai, Masahide Seki, Yaeko Nakajima-Takagi, Takashi Kanamori, Eisuke Iwamoto, Tomoya Muto, Shokichi Tsukamoto, Yusuke Takeda, Chikako Ohwada, Sonoko Misawa, Jun-ichiro Ikeda, Masashi Sanada, Satoshi Kuwabara, Yutaka Suzuki, Emiko Sakaida, Chiaki Nakaseko, Atsushi Iwama
Yusuke Isshiki, Motohiko Oshima, Naoya Mimura, Kensuke Kayamori, Yurie Miyamoto-Nagai, Masahide Seki, Yaeko Nakajima-Takagi, Takashi Kanamori, Eisuke Iwamoto, Tomoya Muto, Shokichi Tsukamoto, Yusuke Takeda, Chikako Ohwada, Sonoko Misawa, Jun-ichiro Ikeda, Masashi Sanada, Satoshi Kuwabara, Yutaka Suzuki, Emiko Sakaida, Chiaki Nakaseko, Atsushi Iwama
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Research Article Hematology

Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis

Abstract

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

Authors

Yusuke Isshiki, Motohiko Oshima, Naoya Mimura, Kensuke Kayamori, Yurie Miyamoto-Nagai, Masahide Seki, Yaeko Nakajima-Takagi, Takashi Kanamori, Eisuke Iwamoto, Tomoya Muto, Shokichi Tsukamoto, Yusuke Takeda, Chikako Ohwada, Sonoko Misawa, Jun-ichiro Ikeda, Masashi Sanada, Satoshi Kuwabara, Yutaka Suzuki, Emiko Sakaida, Chiaki Nakaseko, Atsushi Iwama

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Figure 1

Identification of clonal plasma cells in POEMS syndrome.

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Identification of clonal plasma cells in POEMS syndrome. (A) IGL reperto...
(A) IGL repertoire analysis of plasma cells in POEMS syndrome. The proportions of clonal plasma cells identified by scRNA-Seq are depicted in pie charts. Plasma cells with the same V-(D)-J and CDR3 sequences of the IGL and IGH genes were defined as clonal plasma cells. Numbers in parentheses are the single plasma cell numbers captured by Fluidigm C1. Magenta, clones; gray, nonclones; green, a single plasma cell identified as a clone by its specific amino acid mutations in C. (B) Comparison of the proportion of clones estimated by scRNA-Seq and RNA-Seq of 200 plasma cells. Maroon bars show the proportions of clonal plasma cells identified by scRNA-Seq. Blue bars represent the frequencies of clonal IGL sequence reads in all IGL reads identified by RNA-Seq. (C) POEMS-specific amino acid mutations in the monoclonal IGL VJ domains. Mutated amino acids at positions 38 and 40 (CDR1 and FR2 regions, respectively) are highlighted in red. Germline sequences are highlighted in green. Amino acids are aligned according to international ImMunoGeneTics information system numbering (http://www.imgt.org).