Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide

Kawano,Yawara; Fujiwara,Shiho; Wada,Naoko; Izaki,Mikiko; Yuki,Hiromichi; Okuno,Yutaka; Iyama,Kenichi; Yamasaki,Hiroshi; Sakai,Akira; Mitsuya,Hiroaki; Hata,Hiroyuki

doi:10.3892/ijo.2012.1545

Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide

Authors:
- Yawara Kawano
- Shiho Fujiwara
- Naoko Wada
- Mikiko Izaki
- Hiromichi Yuki
- Yutaka Okuno
- Kenichi Iyama
- Hiroshi Yamasaki
- Akira Sakai
- Hiroaki Mitsuya
- Hiroyuki Hata
View Affiliations

Affiliations: Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan, Department of Surgical Pathology, Kumamoto University Hospital, Kumamoto, Japan, Department of Hematology and Oncology, Kumamoto City Hospital, Kumamoto, Japan, Department of Radiation Life Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan, Department of Hematology, Faculty of Life Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan
Published online on: July 4, 2012 https://doi.org/10.3892/ijo.2012.1545
Pages: 876-884
Copyright: © Kawano et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

CD138 expression is a hallmark of plasma cells and multiple myeloma cells. However, decreased expression of CD138 is frequently observed in plasma cells of myeloma patients, although the clinical significance of this is unclear. To evaluate the significance of low expression of CD138 in MM, we examined the phenotypes of MM cells expressing low levels of CD138. Flow cytometric analysis of primary MM cells revealed a significant decrease in CD138 expression in patients with relapsed/progressive disease compared with untreated MM patients. Patients with low levels of CD138 had a worse overall survival compared with patients with high levels of CD138, in newly diagnosed patients and patients receiving high-dose chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines, KYMM-1 (CD138- low) and KYMM-2 (CD138- high), were established from a single MM patient with decreased CD138 expression. High expression of BCL6 and PAX5, and downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2 cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib was observed. KYMM-2 cells were further divided in CD138+ and CD138- fractions using anti-CD138-coated magnetic beads. CD138- cells sorted from the KYMM-2 cell line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide compared with CD138+ cells. Our observations suggest that low CD138 expression relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity to lenalidomide. The observed distinct characteristics of CD138 low MM cells, suggest this should be recognized as a new clinical entity. Establishment of a treatment strategy for MM cells expressing low levels of CD138 is needed to improve their poor outcome.

View Figures

View References

1	Calame KL: Plasma cells: finding new light at the end of B cell development. Nat Immunol. 2:1103–1108. 2001. View Article : Google Scholar : PubMed/NCBI
2	Dhodapkar MV, Abe E, Theus A, et al: Syndecan-1 is a multi-functional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation. Blood. 91:2679–2688. 1998.PubMed/NCBI
3	Ridley RC, Xiao H, Hata H, Woodliff J, Epstein J and Sanderson RD: Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen. Blood. 81:767–774. 1993.PubMed/NCBI
4	Wijdenes J, Vooijs WC, Clement C, et al: A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1. Br J Haematol. 94:318–323. 1996. View Article : Google Scholar : PubMed/NCBI
5	Zhan F, Huang Y, Colla S, et al: The molecular classification of multiple myeloma. Blood. 108:2020–2028. 2006. View Article : Google Scholar : PubMed/NCBI
6	Ikeda H, Hideshima T, Fulciniti M, et al: The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 15:4028–4037. 2009. View Article : Google Scholar
7	Witzig TE, Kimlinger T, Stenson M and Therneau T: Syndecan-1 expression on malignant cells from the blood and marrow of patients with plasma cell proliferative disorders and B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 31:167–175. 1998. View Article : Google Scholar : PubMed/NCBI
8	Reid S, Yang S, Brown R, et al: Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma. Int J Lab Hematol. 32:e190–e196. 2010. View Article : Google Scholar : PubMed/NCBI
9	Matsui W, Huff CA, Wang Q, et al: Characterization of clonogenic multiple myeloma cells. Blood. 103:2332–2336. 2004. View Article : Google Scholar : PubMed/NCBI
10	Harada H, Kawano MM, Huang N, et al: Phenotypic difference of normal plasma cells from mature myeloma cells. Blood. 81:2658–2663. 1993.PubMed/NCBI
11	Ohmori M, Nagai M, Fujita M, et al: A novel mature B-cell line (DOBIL-6) producing both parathyroid hormone-related protein and interleukin-6 from a myeloma patient presenting with hypercalcaemia. Br J Haematol. 101:688–693. 1998. View Article : Google Scholar : PubMed/NCBI
12	Togawa A, Inoue N, Miyamoto K, Hyodo H and Namba M: Establishment and characterization of a human myeloma cell line (KMM-1). Int J Cancer. 29:495–500. 1982. View Article : Google Scholar : PubMed/NCBI
13	Namba M, Ohtsuki T, Mori M, et al: Establishment of five human myeloma cell lines. In Vitro Cell Dev Biol. 25:723–729. 1989. View Article : Google Scholar : PubMed/NCBI
14	Ohtsuki T, Yawata Y, Wada H, Sugihara T, Mori M and Namba M: Two human myeloma cell lines, amylase-producing KMS-12-PE and amylase-non-producing KMS-12-BM, were established from a patient, having the same chromosome marker, t(11;14)(q13;q32). Br J Haematol. 73:199–204. 1989. View Article : Google Scholar
15	Nilsson K, Bennich H, Johansson SG and Ponten J: Established immunoglobulin producing myeloma (IgE) and lymphoblastoid (IgG) cell lines from an IgE myeloma patient. Clin Exp Immunol. 7:477–489. 1970.PubMed/NCBI
16	Birnie GD: The HL60 cell line: a model system for studying human myeloid cell differentiation. Br J Cancer. (Suppl)9:41–45. 1988.PubMed/NCBI
17	Mahmoud MS, Huang N, Nobuyoshi M, Lisukov IA, Tanaka H and Kawano MM: Altered expression of Pax-5 gene in human myeloma cells. Blood. 87:4311–4315. 1996.PubMed/NCBI
18	Tatetsu H, Ueno S, Hata H, et al: Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter is required for myeloma cell growth. Cancer Res. 67:5328–5336. 2007. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001.
20	Matsuno N, Hoshino K, Nanri T, et al: p15 mRNA expression detected by real-time quantitative reverse transcriptase-polymerase chain reaction correlates with the methylation density of the gene in adult acute leukemia. Leuk Res. 29:557–564. 2005. View Article : Google Scholar
21	Shapiro-Shelef M and Calame K: Regulation of plasma-cell development. Nat Rev Immunol. 5:230–242. 2005. View Article : Google Scholar
22	Lopez-Girona A, Heintel D, Zhang LH, et al: Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol. 154:325–336. 2011. View Article : Google Scholar
23	Li S, Pal R, Monaghan SA, et al: IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 117:5157–5165. 2009.PubMed/NCBI
24	Peceliunas V, Janiulioniene A, Matuzeviciene R and Griskevicius L: Six color flow cytometry detects plasma cells expressing aberrant immunophenotype in bone marrow of healthy donors. Cytometry B Clin Cytom. 80:318–323. 2011. View Article : Google Scholar : PubMed/NCBI
25	Bataille R, Jego G, Robillard N, et al: The phenotype of normal, reactive and malignant plasma cells. Identification of ‘many and multiple myelomas’ and of new targets for myeloma therapy. Haematologica. 91:1234–1240. 2006.PubMed/NCBI
26	Pope B, Brown RD, Gibson J, Yuen E and Joshua D: B7-2-positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy. Blood. 96:1274–1279. 2000.PubMed/NCBI
27	Lin P, Mahdavy M, Zhan F, Zhang HZ, Katz RL and Shaughnessy JD: Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray. Mod Pathol. 17:1217–1222. 2004. View Article : Google Scholar : PubMed/NCBI
28	Hideshima T, Mitsiades C, Ikeda H, et al: A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells. Blood. 115:3772–3775. 2010. View Article : Google Scholar : PubMed/NCBI
29	Fuhler GM, Baanstra M, Chesik D, et al: Bone marrow stromal cell interaction reduces syndecan-1 expression and induces kinomic changes in myeloma cells. Exp Cell Res. 316:1816–1828. 2010. View Article : Google Scholar : PubMed/NCBI
30	Matsui W, Wang Q, Barber JP, et al: Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 68:190–197. 2008. View Article : Google Scholar : PubMed/NCBI
31	Brennan SK, Wang Q, Tressler R, et al: Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms. PLoS One. 5:e124872010. View Article : Google Scholar