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Multiple Myeloma, Gammopathies

Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138−CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis

Leukemia volume 30, pages 1869–1876 (2016)Cite this article

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Abstract

Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138− immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138−CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19–3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26–5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.

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References

  1. Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012; 120: 9–19.

    Article  CAS  Google Scholar 

  2. Bergsagel PL, Mateos MV, Gutierrez NC, Rajkumar SV, San Miguel JF . Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 2013; 121: 884–892.

    Article  CAS  Google Scholar 

  3. Morgan GJ, Walker BA, Davies FE . The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12: 335–348.

    Article  CAS  Google Scholar 

  4. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: e538–e548.

    Article  Google Scholar 

  5. Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia 2014; 28: 981–992.

    Article  CAS  Google Scholar 

  6. Bianchi G, Munshi NC . Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 2015; 125: 3049–3058.

    Article  CAS  Google Scholar 

  7. Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 2014; 5: 2997.

    Article  Google Scholar 

  8. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014; 25: 91–101.

    Article  CAS  Google Scholar 

  9. Corre J, Munshi N, Avet-Loiseau H . Genetics of multiple myeloma: another heterogeneity level? Blood 2015; 125: 1870–1876.

    Article  CAS  Google Scholar 

  10. de Mel S, Lim SH, Tung ML, Chng WJ . Implications of heterogeneity in multiple myeloma. Biomed Res Int 2014; 2014: 232546.

    Article  Google Scholar 

  11. Herve AL, Florence M, Philippe M, Michel A, Thierry F, Kenneth A et al. Molecular heterogeneity of multiple myeloma: pathogenesis, prognosis, and therapeutic implications. J Clin Oncol 2011; 29: 1893–1897.

    Article  Google Scholar 

  12. Szalat R, Munshi NC . Genomic heterogeneity in multiple myeloma. Curr Opin Genet Dev 2015; 30: 56–65.

    Article  CAS  Google Scholar 

  13. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008; 68: 190–197.

    Article  CAS  Google Scholar 

  14. Agarwal JR, Matsui W . Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis. Anticancer Agents Med Chem 2010; 10: 116–120.

    Article  CAS  Google Scholar 

  15. Boucher K, Parquet N, Widen R, Shain K, Baz R, Alsina M et al. Stemness of B-cell progenitors in multiple myeloma bone marrow. Clin Cancer Res 2012; 18: 6155–6168.

    Article  CAS  Google Scholar 

  16. Ghosh N, Matsui W . Cancer stem cells in multiple myeloma. Cancer Lett 2009; 277: 1–7.

    Article  CAS  Google Scholar 

  17. Pilarski LM, Hipperson G, Seeberger K, Pruski E, Coupland RW, Belch AR . Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 2000; 95: 1056–1065.

    CAS  PubMed  Google Scholar 

  18. Yaccoby S . The phenotypic plasticity of myeloma plasma cells as expressed by dedifferentiation into an immature, resilient, and apoptosis-resistant phenotype. Clin Cancer Res 2005; 11: 7599–7606.

    Article  CAS  Google Scholar 

  19. Kotoucek PP, Orfao A . Myeloma stem cell concepts, heterogeneity and plasticity of multiple myeloma. Br J Haematol 2014; 166: 466–467.

    Article  Google Scholar 

  20. Brioli A, Melchor L, Cavo M, Morgan GJ . The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol 2014; 165: 441–454.

    Article  Google Scholar 

  21. Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.

    Article  CAS  Google Scholar 

  22. Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 2014; 28: 384–390.

    Article  Google Scholar 

  23. Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 2013; 24: 289–304.

    Article  CAS  Google Scholar 

  24. Kawano Y, Fujiwara S, Wada N, Izaki M, Yuki H, Okuno Y et al. Multiple myeloma cells expressing low levels of CD138 have an immature phenotype and reduced sensitivity to lenalidomide. Int J Oncol 2012; 41: 876–884.

    Article  CAS  Google Scholar 

  25. Kuroda Y, Sakai A, Okikawa Y, Munemasa S, Katayama Y, Hyodo H et al. The maturation of myeloma cells correlates with sensitivity to chemotherapeutic agents. Int J Hematol 2005; 81: 335–341.

    Article  CAS  Google Scholar 

  26. Otsuka A, Levesque MP, Dummer R, Kabashima K . Hedgehog signaling in basal cell carcinoma. J Dermatol Sci 2015; 78: 95–100.

    Article  CAS  Google Scholar 

  27. Ruiz i Altaba A . Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci Signal 2011; 4: pt9.

    Article  Google Scholar 

  28. Ruiz i Altaba A, Sanchez P, Dahmane N . Gli and hedgehog in cancer: tumors, embryos and stem cells. Nat Rev Cancer 2002; 2: 361–372.

    Article  CAS  Google Scholar 

  29. Satheesha S, Manzella G, Bovay A, Casanova EA, Bode PK, Belle R et al. Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma. Oncogene 2016; 35: 2020–2030.

    Article  CAS  Google Scholar 

  30. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776–779.

    Article  CAS  Google Scholar 

  31. Varjosalo M, Taipale J . Hedgehog: functions and mechanisms. Genes Dev 2008; 22: 2454–2472.

    Article  CAS  Google Scholar 

  32. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008; 455: 406–410.

    Article  CAS  Google Scholar 

  33. Wong SY, Reiter JF . The primary cilium at the crossroads of mammalian hedgehog signaling. Curr Top Dev Biol 2008; 85: 225–260.

    Article  CAS  Google Scholar 

  34. Briscoe J, Therond PP . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013; 14: 416–429.

    Article  Google Scholar 

  35. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048–4053.

    Article  CAS  Google Scholar 

  36. Blotta S, Jakubikova J, Calimeri T, Roccaro AM, Amodio N, Azab AK et al. Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma. Blood 2012; 120: 5002–5013.

    Article  CAS  Google Scholar 

  37. Agarwal JR, Wang Q, Tanno T, Rasheed Z, Merchant A, Ghosh N et al. Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma. Mol Cancer Ther 2014; 13: 1873–1881.

    Article  CAS  Google Scholar 

  38. Liu Z, Xu J, He J, Zheng Y, Li H, Lu Y et al. A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance. Blood 2014; 124: 2061–2071.

    Article  CAS  Google Scholar 

  39. Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Guo GR et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 2007; 13: 944–951.

    Article  CAS  Google Scholar 

  40. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010; 376: 2075–2085.

    Article  CAS  Google Scholar 

  41. Borsi E, Perrone G, Terragna C, Martello M, Dico AF, Solaini G et al. Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma. Oncotarget 2014; 5: 1779–1792.

    Article  Google Scholar 

  42. Li C . Automating dChip: toward reproducible sharing of microarray data analysis. BMC Bioinformatics 2008; 9: 231.

    Article  Google Scholar 

  43. Kanehisa M, Goto S . KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28: 27–30.

    Article  CAS  Google Scholar 

  44. Zhao M, Sun J, Zhao Z . TSGene: a web resource for tumor suppressor genes. Nucleic Acids Res 2013; 41: D970–D976.

    Article  CAS  Google Scholar 

  45. Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003; 102: 4504–4511.

    Article  CAS  Google Scholar 

  46. Pawlyn C, Melchor L, Murison A, Wardell CP, Brioli A, Boyle EM et al. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood 2015; 125: 831–840.

    Article  CAS  Google Scholar 

  47. Boise LH . To Gli or not to Gli. Blood 2014; 124: 2008–2009.

    Article  CAS  Google Scholar 

  48. Chaidos A, Barnes CP, Cowan G, May PC, Melo V, Hatjiharissi E et al. Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma. Blood 2013; 121: 318–328.

    Article  CAS  Google Scholar 

  49. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015; 12: 445–464.

    Article  CAS  Google Scholar 

  50. Pandolfi S, Stecca B . Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy. Expert Rev Mol Med 2015; 17: e5.

    Article  Google Scholar 

  51. Geng L, Wang X . New insight into hedgehog signaling in hematological malignancies. Leuk Lymphoma 2015; 56: 858–865.

    Article  CAS  Google Scholar 

  52. Amakye D, Jagani Z, Dorsch M . Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 2013; 19: 1410–1422.

    Article  CAS  Google Scholar 

  53. Morgan GJ, Kaiser MF . How to use new biology to guide therapy in multiple myeloma. Hematology Am Soc Hematol Educ Program 2012; 2012: 342–349.

    PubMed  Google Scholar 

  54. Merchant AA, Matsui W . Targeting Hedgehog—a cancer stem cell pathway. Clin Cancer Res 2010; 16: 3130–3140.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partly supported by programme funding from AIRC (Associazione Italiana Ricerca sul Cancro) Investigator Research Grant (to MC), RFO (Ricerca Fondamentale Orientata; to MC), BolognAIL (Associazione Italiana contro le Leucemie-Linfomi e Mieloma), Fondazione Guido Berlucchi, Progetto di Ricerca 2014 (to CT) and Progetto Regione-Università 2010/2012L Bolondi (to G Martinelli).

Author contributions

MM and CT designed research, analyzed and interpreted the data and wrote the manuscript; BS, MP and FAD collected samples and data; MM performed gene expression experiments; EB performed immunoblot assays; DR analyzed gene expression results; NT and G Marzocchi provided data on FISH experiments; G Martinelli interpreted the data; EZ, PT, LP and SR provided the clinical data; AP performed statistical correlations; MC critically revised the paper that was approved by the other authors.

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Authors and Affiliations

  1. Department of Experimental Diagnostic and Specialty Medicine (DIMES), Institute of Haematology ‘L. & A. Seràgnoli’, Bologna University School of Medicine, Bologna, Italy

    M Martello, E Borsi, B Santacroce, M Procacci, A Pezzi, F A Dico, G Martinelli, E Zamagni, P Tacchetti, L Pantani, N Testoni, G Marzocchi, S Rocchi, B A Zannetti, K Mancuso, M Cavo & C Terragna

  2. Department of Physics and Astronomy (DIFA), University of Bologna, Bologna, Italy

    D Remondini

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Correspondence to M Cavo.

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Martello, M., Remondini, D., Borsi, E. et al. Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138−CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis. Leukemia 30, 1869–1876 (2016). https://doi.org/10.1038/leu.2016.77

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