Skip to main content

Advertisement

SpringerLink
Log in

Expression of Certain Leukemia/Lymphoma Related microRNAs and its Correlation with Prognosis in Childhood Acute Lymphoblastic Leukemia

  • Research
  • Published:
Pathology & Oncology Research

Abstract

In spite of the improved efficacy of therapy, it still fails in 15–20 % of childhood acute lymphoblastic leukemia (ALL) patients. Recently, altered expression of certain miRNAs (miRs) have been described in ALL with potential effect on prognosis. Presence of certain miRs (miRNA-16, −21, −24, −29b, −128b, −142-3p, −155, −223) was characterized in human lymphoma and leukemia cells by real-time PCR. Expression of miRs in pediatric ALL patients (n = 24) was measured before chemotherapy, at conventional response checkpoints and at relapse. Correlation between altered miR expression and response to prednisolone at day 8 of therapy and long term prognosis was statistically analysed. Overexpression of “oncomiR/inflammamiR”-21 – which is characteristic in different tumors—was missing in human ALL cells. However, higher expression of miR-128b and lower expression of miR-223 is generally characteristic for human ALL cell lines and ALL cells isolated from pediatric patients. Correlation was shown between miR-128b expression and prognosis, prednisolone response and survival data in childhood ALL. Expression of miR-128b and miR-223—both are leukemia specific—changed in parallel with percentage of bone marrow blasts in remission and during relapse. Therefore, we suggest that overexpression of miR-128b and downregulation of miR-223 shows a significant correlation with treatment response and prognosis in childhood ALL.

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
Fig. 3

Similar content being viewed by others

References

  1. Kaatsch P (2010) Epidemiology of childhood cancer. Cancer Treat Rev 36:277–285

    Article  PubMed  Google Scholar 

  2. Pui CH, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166–178

    Article  CAS  PubMed  Google Scholar 

  3. Baranwal S, Alahari SK (2010) miRNA control of tumor cell invasion and metastasis. Int J Cancer 126:1283–1290

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Shin VY, Chu KM (2014) MiRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol 20:10432–10439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Zhu J, Zheng Z, Wang J, Sun J, Wang P, Cheng X, Fu L, Zhang L, Wang Z, Li Z (2014) Different miRNA expression profiles between human breast cancer tumors and serum. Front Genet 5:149

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Lawrie CH (2013) MicroRNAs in hematological malignancies. Blood Rev 27:143–154

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Lee CG (2009) MicroRNA and cancer-focus on apoptosis. J Cell Mol Med 13:12–23

    Article  PubMed Central  PubMed  Google Scholar 

  9. Dong C, Ji M, Ji C (2009) MicroRNAs and their potential target genes in leukemia pathogenesis. Cancer Biol Ther 8:200–205

    Article  CAS  PubMed  Google Scholar 

  10. So AY, Zhao JL, Baltimore D (2013) The Yin and Yang of microRNAs: leukemia and immunity. Immunol Rev 253:129–145

    Article  PubMed Central  PubMed  Google Scholar 

  11. Schotte D, Akbari Moqadam F, Lange-Turenhout EA, Chen C, van Ijcken WF, Pieters R, den Boer ML (2011) Discovery of new microRNAs by small RNAome deep sequencing in childhood acute lymphoblastic leukemia. Leukemia 25:1389–1399

    Article  CAS  PubMed  Google Scholar 

  12. Rainer J, Ploner C, Jesacher S, Ploner A, Eduardoff M, Mansha M, Wasim M, Panzer-Grümayer R, Trajanoski Z, Niederegger H, Kofler R (2009) Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia. Leukemia 23:746–752

    Article  CAS  PubMed  Google Scholar 

  13. Mi S, Lu J, Sun M, Li Z, Zhang H, Neilly MB, Wang Y, Qian Z, Jin J, Zhang Y, Bohlander SK, Le Beau MM, Larson RA, Golub TR, Rowley JD, Chen J (2007) MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci U S A 104:19971–19976

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. de Oliveira JC, Scrideli CA, Brassesco MS, Morales AG, Pezuk JA, QueirozRdeP YJA, Brandalise SR, Tone LG (2012) Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leuk Res 36:293–298

    Article  PubMed  Google Scholar 

  15. Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, Sun Q, Yan F, Yan C, Li H, Ren X (2014) Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene 533:389–397

    Article  CAS  PubMed  Google Scholar 

  16. Mirnezami AH, Pickard K, Zhamg L, Primrose JN, Packham G (2009) MicroRNAs: key players in carcinogenesis and novel therapeutic targets. Eur J Surg Oncol 35:339–347

    Article  CAS  PubMed  Google Scholar 

  17. Löffler D, Brocke-Heinrich K, Pfeifer G, Stocsits C, Hackemüller J, Kretzschmar AK, Burger R, Gramatzki M, Blumert C, Bauer K, Cvijic H, Ullmann AK, Stadler PF, Horn F (2007) Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 110:1330–1333

    Article  PubMed  Google Scholar 

  18. Jurkovicova D, Magyerkova M, Kulcsar L, Krivjanska M, Krivjansky V, Gibadulinova A, Oveckova I, Chovanec M (2014) miR-155 as a diagnostic and prognostic marker in hematological and solid malignancies. Neoplasma 61:241–251

    Article  CAS  PubMed  Google Scholar 

  19. Seddiki N, Brezar V, Ruffin N, Lévy Y, Swaminathan S (2014) Role of miR-155 in the regulation of lymphocyte immune function and disease. Immunology 142:32–38

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Huang X, Shen Y, Liu M, Bi C, Jiang C, Igbal J, McKeithan TW, Chan WC, Ding SJ, Fu K (2012) Quantitative proteomics reveals that miR-155 regulates the PI3K-AKT pathway in diffuse large B-cell lymphoma. Am J Pathol 181:26–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, Ralfkiaer E, Rickert RC, Gronbaek K, David M (2009) Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med 1:288–295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 105:5166–5171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Zaidi SK, Dowdy CR, van Wijnen AJ, Lian JB, Raza A, Stein JL, Croce CM, Stein GS (2009) Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer Res 69:8249–8255

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM (2009) MicroRNA 29b functions in acute myeloid leukemia. Blood 114:5331–5341

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Zhang YK, Wang H, Leng Y, Li ZL, Yang YF, Xiao FJ, Li QF, Chen XQ, Wang LS (2011) Overexpression of microRNA-29b induces apoptosis of multiple myeloma cells through down regulating Mcl-1. Biochem Biophys Res Commun 414:233–239

    Article  CAS  PubMed  Google Scholar 

  26. Li Y, Wang H, Tao K, Xiao Q, Huang Z, Zhong L, Cao W, Wen J, Fen W (2013) miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein. Exp Cell Res 319:1094–1101

    Article  CAS  PubMed  Google Scholar 

  27. Lv M, Zhang X, Jia H, Li D, Zhang B, Zhang H, Hong M, Jiang T, Jiang Q, Lu J, Huang X, Huang B (2012) An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-alpha and cAMP/PKA pathways. Leukemia 26:769–777

    Article  CAS  PubMed  Google Scholar 

  28. Wang XS, Gong JN, Yu J, Wang F, Zhang XH, Yin XL, Tan ZQ, Luo ZM, Yang GH, Shen C, Zhang JW (2012) MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood 119:4992–5004

    Article  CAS  PubMed  Google Scholar 

  29. Dou L, Li J, Zheng D, Li Y, Gao X, Xu C, Gao L, Wang L, Yu L (2013) MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. Mol Biol Rep 40:6811–6819

    Article  CAS  PubMed  Google Scholar 

  30. Palumbo T, Faucz FR, Azevedo M, Xekouki P, Iliopoulos D, Stratakis CA (2013) Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene 32:1651–1659

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I (2005) A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell 123:819–831

    Article  CAS  PubMed  Google Scholar 

  32. Liu TY, Chen SU, Kuo SH, Cheng AL, Lin CW (2010) E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response. Mod Pathol 23:1507–1517

    Article  CAS  PubMed  Google Scholar 

  33. Mosakhani N, Sarhadi VK, Usvasalo A, Karjalainen-Lindsberg ML, Lahti L, Tuononen K, Saarinen-Pihkala UM, Knuutila S (2012) MicroRNA profiling in pediatric acute lymphoblastic leukemia: novel prognostic tools. Leuk Lymphoma 53:2517–2520

    Article  CAS  PubMed  Google Scholar 

  34. de Oliveira JC, Brassesco MS, Scrideli CA, Tone LG, Narendran A (2012) MicroRNA expression and activity in pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 59:599–604

    Article  PubMed  Google Scholar 

  35. Vigorito E, Kohlhaas S, Lu D, Leyland R (2013) miR-155: an ancient regulator of the immune system. Immunol Rev 253:146–157

    Article  PubMed  Google Scholar 

  36. Akbari Moqadam F, Boer JM, Lange-Turenhout EA, Pieters R, den Boer ML (2014) Altered expression of miR-24, miR-126 and miR-365 does not affect viability of childhood TCF3-rearranged leukemia cells. Leukemia 28:1008–1014

    Article  CAS  PubMed  Google Scholar 

  37. Kaddar T, Chien WW, Bertrand Y, Pages MP, Rouault JP, Salles G, Ffrench M, Magaud JP (2009) Prognostic value of miR-16 expression in childhood acute lymphoblastic leukemia relationships to normal and malignant lymphocyte proliferation. Leuk Res 33:1217–1223

    Article  CAS  PubMed  Google Scholar 

  38. Mott JL, Kurita S, Cazanave SC, Bronk SF, Werneburg NW, Fernandez-Zapico ME (2010) Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB. J Cell Biochem 110:1155–1164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mraz M, Kipps TJ (2013) MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. Leuk Lymphoma 54:1836–1839

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Xi Y, Li J, Zan L, Wang J, Wang G, Ning Y (2013) Micro-RNA-16 expression in paraffin-embedded specimen correlates with overall survival of T-lymphoblastic lymphoma/leukemia. Hum Pathol 44:1011–1016

    Article  CAS  PubMed  Google Scholar 

  41. Mishra PJ, Humeniuk R, Mishra PJ, Longo-Sorbello GS, Banerjee D, Bertino JR (2007) A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci U S A 104:13513–13518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Han BW, Feng DD, Li ZG, Luo XQ, Zhang H, Li XJ, Zhang XJ, Zheng LL, Zheng CW, Lin KY, Zhang P, Xu L, Chen YQ (2011) A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL. Hum Mol Genet 20:4903–4915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Zhang H, Luo XQ, Zhang P, Huang LB, Zheng YS, Wu J, Zhou H, Qu LH, Xu L, Chen YQ (2009) MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia. PLoS One 4:e7826

    Article  PubMed Central  PubMed  Google Scholar 

  44. Alqurashi N, Hashimi SM, Wei MQ (2013) Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics. Int J Mol Sci 14:3874–3900

  45. Jia CY, Li HH, Zhu XC, Dong YW, Fu D, Zhao QL, Wu W, Wu XZ (2011) MiR-223 suppresses cell proliferation by targeting IGF-1R. PLoS One 6:e27008

  46. Wang Y, Li Z, He C, Dongmei W, Xianggui Y, Jianjun C, Jie J (2010) MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis 44:191–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Kotani A, Ha D, Hsieh J, Rao PK, Schotte D, den Boer ML, Armstrong SA, Lodish HF (2009) miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221. Blood 114:4169–4178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Nemes K, Sebestyén A, Márk A, Hajdu M, Kenessey I, Sticz T, Nagy E, Barna G, Váradi Z, Kovács G, Kopper L, Csóka M (2013) Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic leukemia (ALL). PLoS One 8:e59335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Gézáné Csorba, András Weiperth, István Kenessey, Csaba Bödör, Tibor Füle, Hajnalka Rajnai for discussion and technical assistance. CCRF-CEM, Nalm6 and Mn60 ALL cell lines were a kind gift of Edit Buzás and Beáta Scholtz from cell culture laboratories at Semmelweis University, Budapest, and The Medical and Health Science Centre, University of Debrecen. The work was supported by Sebestyén A. and Kopper L. OTKA projects (K68341, K81624, K84262) of the Hungarian Academy of Sciences.

Conflict of interest

We declare that all authors have no financial or other conflict of interest that might bias their work.

Author information

Authors and Affiliations

  1. 2nd Department of Pediatrics, Semmelweis University, Budapest, 1094, Tűzoltó u. 7-9., Hungary

    Karolina Nemes, Monika Csóka, Zsófia Váradi & Gábor Kovács

  2. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Üllői út 26., Hungary

    Karolina Nemes, Noémi Nagy, Ágnes Márk, Titanilla Dankó, László Kopper & Anna Sebestyén

  3. Tumor Progression Research Group of Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, 1085, Üllői út 26., Hungary

    Anna Sebestyén

Authors
  1. Karolina Nemes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika Csóka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noémi Nagy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ágnes Márk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zsófia Váradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Titanilla Dankó
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gábor Kovács
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. László Kopper
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Sebestyén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Csóka.

Additional information

Karolina Nemes and Monika Csóka contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nemes, K., Csóka, M., Nagy, N. et al. Expression of Certain Leukemia/Lymphoma Related microRNAs and its Correlation with Prognosis in Childhood Acute Lymphoblastic Leukemia. Pathol. Oncol. Res. 21, 597–604 (2015). https://doi.org/10.1007/s12253-014-9861-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-014-9861-z

Keywords

Search

Navigation