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Acute Leukemias

MicroRNA expression at diagnosis adds relevant prognostic information to molecular categorization in patients with intermediate-risk cytogenetic acute myeloid leukemia

Leukemia volume 28, pages 804–812 (2014)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome-related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR-196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups.

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References

  1. Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012; 120: 2963–2972.

    Article  CAS  PubMed  Google Scholar 

  2. Döhner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    Article  PubMed  Google Scholar 

  3. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    Article  CAS  PubMed  Google Scholar 

  4. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  PubMed  Google Scholar 

  5. Chen J, Odenike O, Rowley JD . Leukaemogenesis: more than mutant genes. Nat Rev Cancer 2010; 10: 23–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 2009; 113: 6411–6418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schotte D, Pieters R, Den Boer M . MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 2011; 26: 1–12.

    Article  PubMed  Google Scholar 

  8. Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T et al. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS One 2008; 3: e2141.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Lowenberg B . MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 2008; 111: 5078–5085.

    Article  CAS  PubMed  Google Scholar 

  10. Diaz-Beya M, Navarro A, Ferrer G, Diaz T, Gel B, Camos M et al. Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene. Leukemia 2012; 27: 595–603.

    Article  PubMed  Google Scholar 

  11. Marcucci G, Mrozek K, Radmacher MD, Garzon R, Bloomfield CD . The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 2011; 117: 1121–1129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA 2008; 105: 3945–3950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marcucci G, Radmacher MD, Maharry K, Mrozek K, Ruppert AS, Paschka P et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1919–1928.

    Article  CAS  PubMed  Google Scholar 

  14. Marcucci G, Maharry K, Radmacher MD, Mrozek K, Vukosavljevic T, Paschka P et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol 2008; 26: 5078–5087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 2008; 111: 3183–3189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA 2008; 105: 15535–15540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li Z, Huang H, Chen P, He M, Li Y, Arnovitz S et al. miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nat Commun 2012; 3: 688.

    PubMed  PubMed Central  Google Scholar 

  18. Sun SM, Rockova V, Bullinger L, Dijkstra MK, Dohner H, Lowenberg B et al. The prognostic relevance of miR-212 expression with survival in cytogenetically and molecularly heterogeneous AML. Leukemia 2012; 27: 100–106.

    Article  PubMed  Google Scholar 

  19. Schwind S, Maharry K, Radmacher MD, Mrozek K, Holland KB, Margeson D et al. Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28: 5257–5264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eisfeld AK, Marcucci G, Maharry K, Schwind S, Radmacher MD, Nicolet D et al. miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia. Blood 2012; 120: 249–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Garzon R, Croce CM . MicroRNAs in normal and malignant hematopoiesis. Curr Opin Hematol 2008; 15: 352–358.

    Article  CAS  PubMed  Google Scholar 

  22. Vasilatou D, Papageorgiou S, Pappa V, Papageorgiou E, Dervenoulas J . The role of microRNAs in normal and malignant hematopoiesis. Eur J Haematol 2010; 84: 1–16.

    Article  CAS  PubMed  Google Scholar 

  23. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834–838.

    Article  CAS  PubMed  Google Scholar 

  24. Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.

    Article  CAS  PubMed  Google Scholar 

  25. Agirre X, Martínez-Climent JÁ, Odero M, Prósper F . Epigenetic regulation of miRNA genes in acute leukemia. Leukemia 2011; 26: 395–403.

    Article  PubMed  Google Scholar 

  26. Shaham L, Binder V, Gefen N, Borkhardt A, Izraeli S . MiR-125 in normal and malignant hematopoiesis. Leukemia 2012; 26: 2011–2018.

    Article  CAS  PubMed  Google Scholar 

  27. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    Article  CAS  PubMed  Google Scholar 

  28. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–3620.

    Article  CAS  PubMed  Google Scholar 

  29. Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004; 22: 624–633.

    Article  PubMed  Google Scholar 

  30. Navarro A, Marrades RM, Vinolas N, Quera A, Agusti C, Huerta A et al. MicroRNAs expressed during lung cancer development are expressed in human pseudoglandular lung embryogenesis. Oncology 2009; 76: 162–169.

    Article  CAS  PubMed  Google Scholar 

  31. Simon R, Lam A, Li MC, Ngan M, Menenzes S, Zhao Y . Analysis of gene expression data using BRB-ArrayTools. Cancer Inform 2007; 3: 11–17.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  33. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  34. Kanda Y . Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2012; 48: 452–458.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  PubMed Central  Google Scholar 

  37. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rücker F, Russ A, Cocciardi S, Kett H, Schlenk R, Botzenhardt U et al. Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance. Leukemia 2012; 27: 353–361.

    Article  PubMed  Google Scholar 

  39. Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 2009; 113: 3314–3322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Danen-van Oorschot AA, Kuipers JE, Arentsen‐Peters S, Schotte D, de Haas V, Trka J et al. Differentially expressed miRNAs in cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Pediatr Blood Cancer 2012; 58: 715–721.

    Article  PubMed  Google Scholar 

  41. Scheffer AR, Holdenrieder S, Kristiansen G, von Ruecker A, Muller SC, Ellinger J . Circulating microRNAs in serum: novel biomarkers for patients with bladder cancer? World J Urol 2012 doi:10.1007/s00345-012-1010-2.

    Article  PubMed  Google Scholar 

  42. Navarro A, Diaz T, Martinez A, Gaya A, Pons A, Gel B et al. Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma. Blood 2009; 114: 2945–2951.

    Article  CAS  PubMed  Google Scholar 

  43. Wu S, Lin Y, Xu D, Chen J, Shu M, Zhou Y et al. MiR-135a functions as a selective killer of malignant glioma. Oncogene 2012; 31: 3866–3874.

    Article  CAS  PubMed  Google Scholar 

  44. Yamada Y, Hidaka H, Seki N, Yoshino H, Yamasaki T, Itesako T et al. Tumor-suppressive microRNA-135a inhibits cancer cell proliferation by targeting the c-MYC oncogene in renal cell carcinoma. Cancer Sci 2012; 104: 304–312.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 2008; 68: 5795–5802.

    Article  CAS  PubMed  Google Scholar 

  46. Liu S, Guo W, Shi J, Li N, Yu X, Xue J et al. MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol 2012; 56: 389–396.

    Article  CAS  PubMed  Google Scholar 

  47. Chen Y, Zhang J, Wang H, Zhao J, Xu C, Du Y et al. miRNA-135a promotes breast cancer cell migration and invasion by targeting HOXA10. BMC Cancer 2012; 12: 111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhou W, Li X, Liu F, Xiao Z, He M, Shen S et al. MiR-135a promotes growth and invasion of colorectal cancer via metastasis suppressor 1 in vitro. Acta Biochim Biophys Sin 2012; 44: 838–846.

    Article  CAS  PubMed  Google Scholar 

  49. Li C, Nie H, Wang M, Su L, Li J, Yu B et al. MicroRNA-409-3p regulates cell proliferation and apoptosis by targeting PHF10 in gastric cancer. Cancer Lett 2012; 320: 189–197.

    Article  CAS  PubMed  Google Scholar 

  50. Weng C, Dong H, Chen G, Zhai Y, Bai R, Hu H et al. miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett 2012; 323: 171–179.

    Article  CAS  PubMed  Google Scholar 

  51. Tsai KW, Wu CW, Hu LY, Li SC, Liao YL, Lai CH et al. Epigenetic regulation of miR-34b and miR-129 expression in gastric cancer. Int J Cancer 2011; 129: 2600–2610.

    Article  CAS  PubMed  Google Scholar 

  52. Stark MS, Tyagi S, Nancarrow DJ, Boyle GM, Cook AL, Whiteman DC et al. Characterization of the melanoma miRNAome by deep sequencing. PLoS One 2010; 5: e9685.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Schotte D, Akbari Moqadam F, Lange-Turenhout EA, Chen C, van Ijcken WF, Pieters R et al. Discovery of new microRNAs by small RNAome deep sequencing in childhood acute lymphoblastic leukemia. Leukemia 2011; 25: 1389–1399.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research is supported by Sociedad Española de Hematologia y Hemoterapia and by grants from Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III N-2004-FS041085, PI080158, FIS-PI0900547 and PI1100872, and, RETICS RD06/0020/0004, RD12/0036/0010, and RD12/0036/0071 and SDCSD from School of Medicine. Marina Díaz-Beyá is supported by Fundación Española de Hematologia y Hemoterapia. Rut Tejero is an APIF fellow from University of Barcelona.

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Author notes

  1. A Navarro and J Esteve: These authors share the senior authorship.

Authors and Affiliations

  1. Hematology Department, Hospital Clinic, Institut d'Investigacions Bomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    M Díaz-Beyá, M Pratcorona & J Esteve

  2. Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain

    M Díaz-Beyá, S Brunet, J Nomdedéu, M Pratcorona, J Sierra & J Esteve

  3. Hematology Service, Institut d’Investigació Biomèdica Sant Pau. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Banc de Sang i Teixits de Catalunya, Spain

    S Brunet, M Monzo & J Sierra

  4. Laboratory of Hematology Service, Institut d’Investigació Biomèdica Sant Pau. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

    J Nomdedéu

  5. Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain

    R Tejero, T Díaz & A Navarro

  6. Hematology Department, Hospital Clínico, Valencia, Spain

    M Tormo

  7. Hematology Department, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Spain

    J M Ribera

  8. Hematology Department, Hospital Joan XXIII, Tarragona, Spain

    L Escoda

  9. Department of Hematology, Catalan Institute of Oncology (ICO), Hospital Duran i Reynals, Barcelona, Spain

    R Duarte

  10. Hematology Department, Catalan Institute of Oncology (ICO), Girona, Spain

    D Gallardo

  11. Department of Hematology, University Hospital Morales Meseguer, Murcia, Spain

    I Heras

  12. Department of Hematology, Hospital Virgen de la Victoria, Málaga, Spain

    M P Queipo de Llano

  13. Department of Hematology, Hospital de Son Llàtzer, Palma de Mallorca, Spain

    J Bargay

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  1. M Díaz-Beyá
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on behalf of the Cooperative AML group CETLAM (Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias)

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Correspondence to J Esteve.

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Additional information

This research was presented in part as an oral presentation at the 53rd annual meeting of the American Society of Hematology, San Diego, CA, USA, December, 2011 and selected for highlights of ASH 2011.

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Díaz-Beyá, M., Brunet, S., Nomdedéu, J. et al. MicroRNA expression at diagnosis adds relevant prognostic information to molecular categorization in patients with intermediate-risk cytogenetic acute myeloid leukemia. Leukemia 28, 804–812 (2014). https://doi.org/10.1038/leu.2013.281

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