Skip to main content
SpringerLink
Log in

Biological activity of lenalidomide in myelodysplastic syndromes with del5q: results of gene expression profiling from a multicenter phase II study

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

In vitro studies suggest that haploinsufficiency is involved in the pathogenesis of myelodysplastic syndromes (MDS). In patients with del5q cytogenetic abnormality, RPS-14 and microRNAs (miRNAs) play a major role. In a multicenter phase II single-arm trial with lenalidomide in anemic primary del5q MDS patients with low- or int-1 risk IPSS, biological changes from baseline were investigated. Gene expression profiling of selected genes was performed (TaqMan® Low Density Array Fluidic card, Applied Biosystems PRISM® 7900HT) and normalized against the expression of the 18S housekeeping gene from a pool of healthy subjects. Thirty-two patients were evaluated at baseline and after 3 and 6 months of treatment. RPS-14, miR-145, and miR-146 were downregulated at baseline and significantly increased during treatment. Nuclear factor kappa B, IL-6, interferon regulatory factor-1, IFNγ-R2, IL-2, and many genes in the apoptotic pathways (TNF, IL-1B, and IL-10) were upregulated at baseline and significantly downregulated during lenalidomide treatment, while forkhead box P3, FAS, IFNγ, IL-12A, and IL-12B were downregulated at baseline and progressively upregulated during treatment. The crucial role of aberrant immunological pathways and haploinsufficiency in the pathogenesis of del5q MDS is confirmed in the present patient setting. Our results indicate that lenalidomide may act through defined immunological pathways in this condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951

    Article  PubMed  CAS  Google Scholar 

  2. Garcia-Manero G (2011) Myelodysplastic syndromes: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86:490–498

    Article  PubMed  CAS  Google Scholar 

  3. Allampallam K, Shetty V, Mundle S, Dutt D, Kravitz H, Reddy PL, Alvi S, Galili N, Saberwal GS, Anthwal S, Shaikh MW, York A, Raza A (2002) Biological significance of proliferation, apoptosis, cytokines, and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. Int J Hematol 75:289–297

    Article  PubMed  CAS  Google Scholar 

  4. Kitagawa M, Kurata M, Yamamoto K, Abe S, Suzuki S, Umeda S (2011) Molecular pathology of myelodysplastic syndromes: biology of medullary stromal and hematopoietic cells. Mol Med Rep 4:591–596

    CAS  Google Scholar 

  5. Warlick ED, Miller JS (2011) Myelodysplastic syndromes: the role of the immune system in pathogenesis. Leuk Lymphoma 52:2045–2049

    Article  PubMed  CAS  Google Scholar 

  6. Stirewalt DL, Mhyre AJ, Marcondes M, Pogosova-Agadjanyan E, Abbasi N, Radich JP, Deeg HJ (2008) Tumour necrosis factor-induced gene expression in human marrow stroma: clues to the pathophysiology of MDS? Br J Haematol 140:444–453

    Article  PubMed  CAS  Google Scholar 

  7. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, Kundgen A, Lübbert M, Kunzmann R, Giagounidis AA, Aul C, Trümper L, Krieger O, Stauder R, Müller TH, Wimazal F, Valent P, Fonatsch C, Steidl C (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110:4385–4395

    Article  PubMed  CAS  Google Scholar 

  8. Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G (1974) Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature 251:437–438

    Article  PubMed  Google Scholar 

  9. Padron E, Komrokji R, List AF (2011) The 5q− syndrome: biology and treatment. Curr Treat Options Oncol 12:354–368

    Article  PubMed  Google Scholar 

  10. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465

    Article  PubMed  CAS  Google Scholar 

  11. Le Bras F, Sebert M, Kelaidi C, Lamy T, Dreyfus F, Delaunay J, Banos A, Blanc M, Vey N, Schmidt A, Visanica S, Eclache V, Turlure P, Beyne-Rauzy O, Guerci A, Delmer A, de Botton S, Rea D, Fenaux P, Adès L (2011) Treatment by lenalidomide in lower risk myelodysplastic syndrome with 5q deletion-The GFM experience. Leuk Res 35:1444–1448

    Article  PubMed  Google Scholar 

  12. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E (2011) A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118:3765–3776

    Article  PubMed  CAS  Google Scholar 

  13. Jaju RJ, Boultwood J, Oliver FJ, Kostrzewa M, Fidler C, Parker N, McPherson JD, Morris SW, Müller U, Wainscoat JS, Kearney L (1998) Molecular cytogenetic delineation of the critical deleted region in the 5q− syndrome. Genes Chromosom Cancer 22:251–256

    Article  PubMed  CAS  Google Scholar 

  14. Ebert BL (2009) Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia 23:1252–1256

    Article  PubMed  CAS  Google Scholar 

  15. Pellagatti A, Jädersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK, Merup M, Nilsson L, Samuelsson J, Sander B, Wainscoat JS, Boultwood J, Hellström-Lindberg E (2007) Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q− syndrome patients. Proc Natl Acad Sci U S A 104:11406–11411

    Article  PubMed  CAS  Google Scholar 

  16. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR (2008) Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature 451:335–339

    Article  PubMed  CAS  Google Scholar 

  17. Boultwood J, Pellagatti A, Cattan H, Lawrie CH, Giagounidis A, Malcovati L, Della Porta MG, Jädersten M, Killick S, Fidler C, Cazzola M, Hellström-Lindberg E, Wainscoat JS (2007) Gene expression profiling of CD34+ cells in patients with the 5q− syndrome. Br J Haematol 139:578–589

    Article  PubMed  CAS  Google Scholar 

  18. Barlow JL, Drynan LF, Hewett DR, Holmes LR, Lorenzo-Abalde S, Lane AL, Jolin HE, Pannell R, Middleton AJ, Wong SH, Warren AJ, Wainscoat JS, Boultwood J, McKenzie AN (2010) A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q− syndrome. Nat Med 16:59–66

    Article  PubMed  CAS  Google Scholar 

  19. Pellagatti A, Hellström-Lindberg E, Giagounidis A, Perry J, Malcovati L, Della Porta MG, Jädersten M, Killick S, Fidler C, Cazzola M, Wainscoat JS, Boultwood J (2008) Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol 142:57–64

    Article  PubMed  CAS  Google Scholar 

  20. Oliva EN, Cuzzola M, Nobile F, Ronco F, D’Errigo MG, Laganà C, Morabito F, Galimberti S, Cortelezzi A, Aloe Spiriti MA, Specchia G, Poloni A, Breccia M, Ghio R, Finelli C, Iacopino P, Alimena G, Latagliata R (2010) Changes in RPS14 expression levels during lenalidomide treatment in low- and intermediate-1-risk myelodysplastic syndromes with chromosome 5q deletion. Eur J Haematol 85:231–235

    Article  PubMed  CAS  Google Scholar 

  21. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  22. Lodish HF, Zhou B, Liu G, Chen CZ (2008) Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8:120–130

    Article  PubMed  CAS  Google Scholar 

  23. Stahl HF, Fauti T, Ullrich N, Bopp T, Kubach J, Rust W, Labhart P, Alexiadis V, Becker C, Hafner M, Weith A, Lenter MC, Jonuleit H, Schmitt E, Mennerich D (2009) miR-155 inhibition sensitizes CD4+ Th cells for TREG mediated suppression. PLoS One 4(9):e7158

    Article  PubMed  Google Scholar 

  24. Votavova H, Grmanova M, Dostalova Merkerova M, Belickova M, Vasikova A, Neuwirtova R, Cermak J (2010) Differential expression of microRNAs in CD34+ cells of 5q− syndrome. J Hematol Oncol 4:1

    Article  Google Scholar 

  25. Pons A, Nomdedeu B, Navarro A, Gaya A, Gel B, Diaz T, Valera S, Rozman M, Belkaid M, Montserrat E, Monzo M (2009) Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma 50:1854–1859

    Article  PubMed  CAS  Google Scholar 

  26. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells RA, Buckstein R, Lam W, Humphries RK, Karsan A (2010) Identification of miR-145 and miR-146a as mediators of the 5q− syndrome phenotype. Nat Med 16:49–58

    Article  PubMed  CAS  Google Scholar 

  27. Feng Z, Zhang C, Wu R, Hu W (2011) Tumor suppressor p53 meets microRNAs. J Mol Cell Biol 3(1):44–50

    Article  PubMed  CAS  Google Scholar 

  28. Starczynowski D, Karsan A (2010) Deregulation of innate immune signaling in myelodysplastic syndromes is associated with deletion of chromosome arm 5q. Cell Cycle 95:855–856

    Article  Google Scholar 

  29. Starczynowski DT, Karsan A (2010) Innate immune signaling in the myelodysplastic syndromes. Hematol Oncol Clin North Am 24:343–359

    Article  PubMed  Google Scholar 

  30. Kumar MS, Narla A, Nonami A, Mullally A, Dimitrova N, Ball B, McAuley JR, Poveromo L, Kutok JL, Galili N, Raza A, Attar E, Gilliland DG, Jacks T, Ebert BL (2011) Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q− syndrome. Blood 118:4666–4673

    Article  PubMed  CAS  Google Scholar 

  31. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419–425

    Article  PubMed  CAS  Google Scholar 

  32. Gustashaw KM (1991) Chromosome stains. In: Barch MJ (ed) The ACT cytogenetics laboratory manual, 2nd edn. The Association of Cytogenetic Technologists, Raven, New York

    Google Scholar 

  33. Shaffer LG, Tommerup N (2005) An International System for Human Cytogenetic Nomenclature. Karger, Basel

    Google Scholar 

  34. Hod EA, Zhang N, Sokol SA, Wojczyk BS, Francis RO, Ansaldi D, Francis KP, Della-Latta P, Whittier S, Sheth S, Hendrickson JE, Zimring JC, Brittenham GM, Spitalnik SL (2010) Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. Blood 115:4284–4292

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a research funding from Associazione QOL-ONE, Reggio Calabria, Italy and by a funding from Celgene Corporation.

Conflict of interest

ENO has received honoraria from Celgene, Janssen, Novartis, and GlaxoSmithKline; RL has received honoraria from Celgene, Novartis, Bristol-Myers Squibb, and Shire. All other authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Haematology Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, Via Melacrino, 89100, Reggio, Calabria, Italy

    Esther Natalie Oliva, Filippo Rodà & Francesco Nobile

  2. Bone Marrow Transplantation Unit, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, Reggio, Calabria, Italy

    Maria Cuzzola & Carmela Rigolino

  3. Haematology Department, A.O. Sant’Andrea, Rome, Italy

    Maria Antonietta Aloe Spiriti

  4. Haematology Unit, Università Politecnica delle Marche, Ancona, Italy

    Antonella Poloni

  5. Medical Cytogenetics, Azienda Ospedaliera “Bianchi-Melacrino-Morelli”, Reggio, Calabria, Italy

    Carmelo Laganà

  6. Haematology Unit, Azienda Ospedaliera di Cosenza, Cosenza, Italy

    Fortunato Morabito

  7. Department of Oncology, Transplants and Advanced Technologies, St. Chiara Hospital, University of Pisa, Pisa, Italy

    Sara Galimberti

  8. Haematology Unit, San Martino Hospital, Genova, Italy

    Riccardo Ghio

  9. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Agostino Cortelezzi

  10. Haematology Unit, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Catania, Italy

    Giuseppe Alberto Palumbo

  11. Haematology Division, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy

    Grazia Sanpaolo

  12. Department of Haematology, University of Bologna, Bologna, Italy

    Carlo Finelli

  13. Department of Haematology, University of Bari, Bari, Italy

    Alessandra Ricco

  14. Haematology Division, San Giuseppe Moscati Hospital, Avellino, Italy

    Antonio Volpe

  15. Department of Cellular Biotechnology and Haematology, Sapienza University, Sapienza, Rome, Italy

    Massimo Breccia, Giuliana Alimena & Roberto Latagliata

Authors
  1. Esther Natalie Oliva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Cuzzola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Antonietta Aloe Spiriti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonella Poloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carmelo Laganà
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carmela Rigolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fortunato Morabito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sara Galimberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Riccardo Ghio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Agostino Cortelezzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giuseppe Alberto Palumbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Grazia Sanpaolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carlo Finelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alessandra Ricco
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Antonio Volpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Filippo Rodà
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Massimo Breccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Giuliana Alimena
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Francesco Nobile
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Roberto Latagliata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Esther Natalie Oliva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oliva, E.N., Cuzzola, M., Aloe Spiriti, M.A. et al. Biological activity of lenalidomide in myelodysplastic syndromes with del5q: results of gene expression profiling from a multicenter phase II study. Ann Hematol 92, 25–32 (2013). https://doi.org/10.1007/s00277-012-1569-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-012-1569-0

Keywords

Search

Navigation