OpenLB
Open Library of Bioscience
Advanced Search
FEBS letters
02, 2020;594 (3): 452-465.

Single-cell RNA sequencing reveals chemokine self-feeding of myeloma cells promotes extramedullary metastasis.

Shuang Geng, Jing Wang, Xiannian Zhang, Jia-Jia Zhang, Fan Wu, Yuhong Pang, Yuping Zhong, Jianbin Wang, Wenming Wang, Xiaoqing Lyu, Yanyi Huang, Hongmei Jing
Author Information
  1. Shuang Geng: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  2. Jing Wang: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  3. Xiannian Zhang: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  4. Jia-Jia Zhang: Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  5. Fan Wu: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  6. Yuhong Pang: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  7. Yuping Zhong: Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  8. Jianbin Wang: School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  9. Wenming Wang: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  10. Xiaoqing Lyu: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  11. Yanyi Huang: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China.
  12. Hongmei Jing: Department of Hematology, Biodynamic Optical Imaging Center (BIOPIC) and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China. ORCID
PMID: 31561267 DOI: 10.1002/1873-3468.13623

Abstract

In this study, we aimed to determine the mechanisms underlying the initial extramedullary translocation of myeloma cells from bone marrow into peripheral blood. We found that clonal circulating plasma cells (cPCs) are more frequently detected by flow cytometry in extramedullary plasmacytoma (EMP) patients and worsen their prognosis. It is technically much easier to collect single cPCs using FACS than it is to perform EMP biopsy. Therefore, combining EMP imaging with cPC detection may be a promising strategy for prognostic stratification. Here, using single-cell transcriptome analysis, we found that the chemokine CXCL12, a key molecule involved in CXCR4-dependent cell retention in the bone marrow, is abnormally upregulated in cPCs and might initially enable cPCs to evade bone marrow retention and translocate into the bloodstream.

Keywords

chemokine self-feeding circulating plasma cells extramedullary plasmacytoma multiple myeloma

References

  1. Becker N (2011) Epidemiology of multiple myeloma. Recent Results Cancer Res 183, 25-35.
  2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A and Flowers CR (2016) 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin 66, 443-459.
  3. Rajkumar SV (2015) Evolving diagnostic criteria for multiple myeloma. Hematology Am Soc Hematol Educ Program 2015, 272-278.
  4. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P et al. (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15, e538-e548.
  5. Blade J, Fernandez de Larrea C, Rosinol L, Cibeira MT, Jimenez R and Powles R (2011) Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 29, 3805-3812.
  6. Lu J, Lu J, Chen W, Huo Y, Huang X, Hou J and Chinese Medical Doctor Association Hematology Branch (2014) Clinical features and treatment outcome in newly diagnosed Chinese patients with multiple myeloma: results of a multicenter analysis. Blood Cancer J 4, e239.
  7. Lee SE, Kim JH, Jeon YW, Yoon JH, Shin SH, Eom KS, Kim YJ, Kim HJ, Lee S, Cho SG et al. (2015) Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma. Ann Hematol 94, 445-452.
  8. Molica S (2012) Extramedullary involvement: an emerging problem in multiple myeloma. Clin Adv Hematol Oncol 10, 268-269.
  9. Kakati BR, Krishna K, Krishna SG, Sharma SG, Sanathkumar N and Rego RF (2012) Extensive extramedullary disease involving the colon in multiple myeloma: a case report and review of literature. J Gastrointest Cancer 43, 379-381.
  10. Blade J, de Larrea CF and Rosinol L (2012) Extramedullary involvement in multiple myeloma. Haematologica 97, 1618-1619.
  11. Zhu Z, Li C, Yang S, Tian R, Wang J, Yuan Q, Dong H, He Z, Wang S and Li Z (2016) Dynamics of the transcriptome during human spermatogenesis: predicting the potential key genes regulating male gametes generation. Sci Rep 6, 19069.
  12. Yang Y, Wang H, Chang KH, Qu H, Zhang Z, Xiong Q, Qi H, Cui P, Lin Q, Ruan X et al. (2013) Transcriptome dynamics during human erythroid differentiation and development. Genomics 102, 431-441.
  13. Lohr JG, Kim S, Gould J, Knoechel B, Drier Y, Cotton MJ, Gray D, Birrer N, Wong B, Ha G et al. (2016) Genetic interrogation of circulating multiple myeloma cells at single-cell resolution. Sci Transl Med 8, 363ra147.
  14. Palumbo A, Sezer O, Kyle R, Miguel JS, Orlowski RZ, Moreau P, Niesvizky R, Morgan G, Comenzo R, Sonneveld P et al. (2009) International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 23, 1716-1730.
  15. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Bladé J, Mateos MV et al. (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17, e328-e346.
  16. Picelli S, Faridani OR, Bjorklund AK, Winberg G, Sagasser S and Sandberg R (2014) Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc 9, 171-181.
  17. Patro R, Duggal G, Love MI, Irizarry RA and Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods 14, 417-419.
  18. Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Gertz MA, Lacy MQ, Lust JA, Dispenzieri A, Greipp PR, Kyle RA et al. (2005) Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood 106, 2276-2279.
  19. Li J, Wang N, Tesfaluul N, Gao X, Liu S and Yue B (2017) Prognostic value of circulating plasma cells in patients with multiple myeloma: a meta-analysis. PLoS One 12, e0181447.
  20. Kumar S, Kimlinger T and Morice W (2010) Immunophenotyping in multiple myeloma and related plasma cell disorders. Best Pract Res Clin Haematol 23, 433-451.
  21. Ramsköld D, Luo S, Wang YC, Li R, Deng Q, Faridani OR, Daniels GA, Khrebtukova I, Loring JF, Laurent LC et al. (2012) Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat Biotechnol 30, 777-782.
  22. Picelli S, Bjorklund AK, Faridani OR, Sagasser S, Winberg G and Sandberg R (2013) Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat Methods 10, 1096-1098.
  23. Matthes T, Manfroi B, Zeller A, Dunand-Sauthier I, Bogen B and Huard B (2015) Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow. Leukemia 29, 1882-1890.
  24. Jernberg-Wiklund H, Pettersson M, Carlsson M and Nilsson K (1992) Increase in interleukin 6 (IL-6) and IL-6 receptor expression in a human multiple myeloma cell line, U-266, during long-term in vitro culture and the development of a possible autocrine IL-6 loop. Leukemia 6, 310-318.
  25. Suematsu S, Hibi M, Sugita T, Saito M, Murakami M, Matsusaka T, Matsuda T, Hirano T, Taga T and Kishimoto T (1990) Interleukin 6 (IL-6) and its receptor (IL-6R) in myeloma/plasmacytoma. Curr Top Microbiol Immunol 166, 13-22.
  26. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, Powell J, Dave S, Yu X, Zhao H et al. (2008) IRF4 addiction in multiple myeloma. Nature 454, 226-231.
  27. Borson ND, Lacy MQ and Wettstein PJ (2002) Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma. Blood 100, 4629-4639.
  28. Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H et al. (2012) Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. Blood 119, 5772-5781.
  29. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F and Glimcher LH (2001) Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300-307.
  30. Freund GG, Kulas DT, Way BA and Mooney RA (1994) Functional insulin and insulin-like growth factor-1 receptors are preferentially expressed in multiple myeloma cell lines as compared to B-lymphoblastoid cell lines. Cancer Res 54, 3179-3185.
  31. Borset M, Hjorth-Hansen H, Seidel C, Sundan A and Waage A (1996) Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 88, 3998-4004.
  32. Georgii-Hemming P, Wiklund HJ, Ljunggren O and Nilsson K (1996) Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood 88, 2250-2258.
  33. Dankbar B, Padró T, Leo R, Feldmann B, Kropff M, Mesters RM, Serve H, Berdel WE and Kienast J (2000) Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 95, 2630-2636.
  34. Ortiz-Zapater E, Pineda D, Martínez-Bosch N, Fernández-Miranda G, Iglesias M, Alameda F, Moreno M, Eliscovich C, Eyras E, Real FX et al. (2011) Key contribution of CPEB4-mediated translational control to cancer progression. Nat Med 18, 83-90.
  35. Zhang K, Xu Z and Sun Z (2015) Identification of the key genes connected with plasma cells of multiple myeloma using expression profiles. Onco Targets Ther 8, 1795-1803.
  36. Gutiérrez NC, Ocio EM, de Las Rivas J, Maiso P, Delgado M, Fermiñán E, Arcos MJ, Sánchez ML, Hernández JM and San Miguel JF (2007) Gene expression profiling of B lymphocytes and plasma cells from Waldenstrom's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 21, 541-549.
  37. Daniel J and Liebau E (2014) The ufm1 cascade. Cells 3, 627-638.
  38. Frigyesi I, Adolfsson J, Ali M, Christophersen MK, Johnsson E, Turesson I, Gullberg U, Hansson M and Nilsson B (2014) Robust isolation of malignant plasma cells in multiple myeloma. Blood 123, 1336-1340.
  39. Teng Y, Gao M, Wang J, Kong Q, Hua H, Luo T and Jiang Y (2014) Inhibition of eIF2alpha dephosphorylation enhances TRAIL-induced apoptosis in hepatoma cells. Cell Death Dis 5, e1060.
  40. Mahtouk K, Moreaux J, Hose D, Rème T, Meissner T, Jourdan M, Rossi JF, Pals ST, Goldschmidt H and Klein B (2010) Growth factors in multiple myeloma: a comprehensive analysis of their expression in tumor cells and bone marrow environment using Affymetrix microarrays. BMC Cancer 10, 198.
  41. Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, el Jarari L, Mulligan G, Gregory W, Morgan G et al. (2012) A gene expression signature for high-risk multiple myeloma. Leukemia 26, 2406-2413.
  42. Heuck CJ, Qu P, van Rhee F, Waheed S, Usmani SZ, Epstein J, Zhang Q, Edmondson R, Hoering A, Crowley J et al. (2014) Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma. Leukemia 28, 2410-2413.
  43. Beider K, Nagler A, Wald O, Franitza S, Dagan-Berger M, Wald H, Giladi H, Brocke S, Hanna J, Mandelboim O et al. (2003) Involvement of CXCR42 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood 102, 1951-1958.
  44. Suratt BT, Petty JM, Young SK, Malcolm KC, Lieber JG, Nick JA, Gonzalo JA, Henson PM and Worthen GS (2004) Role of the CXCR43/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood 104, 565-571.
  45. Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, Sanchez-Martin M, Tsirigos A, Littman DR, Ferrando AA et al. (2015) CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell 27, 755-768.
  46. Liu KK and Dorovini-Zis K (2009) Regulation of CXCL12 and CXCR45 expression by human brain endothelial cells and their role in CD4+ and CD8+ T cell adhesion and transendothelial migration. J Neuroimmunol 215, 49-64.
  47. Schajnovitz A, Itkin T, D'Uva G, Kalinkovich A, Golan K, Ludin A, Cohen D, Shulman Z, Avigdor A, Nagler A et al. (2011) CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nat Immunol 12, 391-398.
  48. Grépin R, Guyot M, Giuliano S, Boncompagni M, Ambrosetti D, Chamorey E, Scoazec JY, Negrier S, Simonnet H and Pagès G (2014) The CXCL7/CXCR48/2 axis is a key driver in the growth of clear cell renal cell carcinoma. Cancer Res 74, 873-883.
  49. Gonsalves WI, Rajkumar SV, Gupta V, Morice WG, Timm MM, Singh PP, Dispenzieri A, Buadi FK, Lacy MQ, Kapoor P et al. (2014) Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma. Leukemia 28, 2060-2065.
  50. Ginsberg DM (1962) Circulating plasma cells in multiple myeloma. A method for detection and review of the problem. Ann Intern Med 57, 843-846.
  51. Zandecki M, Facon T, Preudhomme C, Canis F, Izydorczyk V, Lovi V, Hammad M, Bauters F and Cosson A (1994) Significance of circulating plasma cells in multiple myeloma. Leuk Lymphoma 14, 491-496.
  52. Peceliunas V, Janiulioniene A, Matuzeviciene R, Zvirblis T and Griskevicius L (2012) Circulating plasma cells predict the outcome of relapsed or refractory multiple myeloma. Leuk Lymphoma 53, 641-647.
  53. Gonsalves WI, Morice WG, Rajkumar V, Gupta V, Timm MM, Dispenzieri A, Buadi FK, Lacy MQ, Singh PP, Kapoor P et al. (2014) Quantification of clonal circulating plasma cells in relapsed multiple myeloma. Br J Haematol 167, 500-505.
  54. Kumar S, Rajkumar SV, Kyle RA, Lacy MQ, Dispenzieri A, Fonseca R, Lust JA, Gertz MA, Greipp PR and Witzig TE (2005) Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J Clin Oncol 23, 5668-5674.

MeSH Term

Aged
Bone Marrow
Chemokines
Female
Humans
Male
Middle Aged
Multiple Myeloma
Neoplasm Metastasis
Phenotype
Prognosis
Sequence Analysis, RNA
Single-Cell Analysis

Chemicals

Chemokines
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000032 (Single cell RNA sequencing revealed a chemokine self-feeding of myeloma cells for extramedullary metastasis)

Word Cloud

Similar Articles

Cited By