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Acute Leukemias

B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells

Leukemia volume 26, pages 2224–2232 (2012)Cite this article

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Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.

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References

  1. Cobaleda C, Sanchez-Garcia I . B-cell acute lymphoblastic leukaemia: towards understanding its cellular origin. Bioessays 2009; 31: 600–609.

    Article  PubMed  Google Scholar 

  2. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524–15529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  4. Shi XB, Xue L, Yang J, Ma AH, Zhao J, Xu M et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci USA 2007; 104: 19983–19988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J Exp Med 2008; 205: 2499–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang H, Luo XQ, Zhang P, Huang LB, Zheng YS, Wu J et al. MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia. PLoS One 2009; 4: e7826.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gefen N, Binder V, Zaliova M, Linka Y, Morrow M, Novosel A et al. Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53. Leukemia 2010; 24: 89–96.

    Article  CAS  PubMed  Google Scholar 

  8. Sonoki T, Iwanaga E, Mitsuya H, Asou N . Insertion of microRNA-125b-1, a human homologue of lin-4, into a rearranged immunoglobulin heavy chain gene locus in a patient with precursor B-cell acute lymphoblastic leukemia. Leukemia 2005; 19: 2009–2010.

    Article  CAS  PubMed  Google Scholar 

  9. Chapiro E, Russell LJ, Struski S, Cavé H, Radford-Weiss I, Valle VD et al. A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia 2010; 24: 1362–1364.

    Article  CAS  PubMed  Google Scholar 

  10. Tassano E, Acquila M, Tavella E, Micalizzi C, Panarello C, Morerio C et al. MicroRNA-125b-1 and BLID upregulation resulting from a novel IGH translocation in childhood B-Cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer 2010; 49: 682–687.

    Article  CAS  PubMed  Google Scholar 

  11. Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev 2009; 23: 862–876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pottier N, Maurin T, Chevalier B, Puisségur MP, Lebrigand K, Robbe-Sermesant K et al. Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions. PLoS One 2009; 4: e6718.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Puisségur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ 2011; 18: 465–478.

    Article  PubMed  Google Scholar 

  14. Le Brigand K, Robbe-Sermesant K, Mari B, Barbry P . MiRonTop: mining microRNAs targets across large scale gene expression studies. Bioinformatics 2010; 26: 3131–3132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Webb CF, Bryant J, Popowski M, Allred L, Kim D, Harriss J et al. The ARID family transcription factor bright is required for both hematopoietic stem cell and B lineage development. Mol Cell Biol 2011; 31: 1041–1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nixon JC, Ferrell S, Miner C, Oldham AL, Hochgeschwender U, Webb CF . Transgenic mice expressing dominant-negative bright exhibit defects in B1 B cells. J Immunol 2008; 181: 6913–6922.

    Article  CAS  PubMed  Google Scholar 

  17. An G, Miner CA, Nixon JC, Kincade PW, Bryant J, Tucker PW et al. Loss of Bright/ARID3a function promotes developmental plasticity. Stem Cells 2010; 28: 1560–1567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bousquet M, Broccardo C, Quelen C, Meggetto F, Kuhlein E, Delsol G et al. A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5. Blood 2007; 109: 3417–3423.

    Article  CAS  PubMed  Google Scholar 

  19. Fazio G, Palmi C, Rolink A, Biondi A, Cazzaniga G . PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells. Cancer Res 2008; 68: 181–189.

    Article  CAS  PubMed  Google Scholar 

  20. Herrscher RF, Kaplan MH, Lelsz DL, Das C, Scheuermann R, Tucker PW . The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describes a new DNA-binding protein family. Genes Dev 1995; 9: 3067–3082.

    Article  CAS  PubMed  Google Scholar 

  21. Sinha AU, Kaimal V, Chen J, Jegga AG . Dissecting microregulation of a master regulatory network. BMC Genomics 2008; 9: 88.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Filipowicz W, Bhattacharyya SN, Sonenberg N . Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9: 102–114.

    Article  CAS  PubMed  Google Scholar 

  23. Tili E, Michaille JJ, Calin GA . Expression and function of micro-RNAs in immune cells during normal or disease state. Int J Med Sci 2008; 5: 73–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 2007; 179: 5082–5089.

    Article  CAS  PubMed  Google Scholar 

  25. Schickel R, Boyerinas B, Park SM, Peter ME . MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 2008; 27: 5959–5974.

    Article  CAS  PubMed  Google Scholar 

  26. Chaudhuri AA, So AY, Mehta A, Minisandram A, Sinha N, Jonsson VD et al. Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A. Proc Natl Acad Sci USA 2012; 109: 4233–4238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. O'Connell RM, Chaudhuri AA, Rao DS, Gibson WS, Balazs AB, Baltimore D . MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output. Proc Natl Acad Sci USA 2010; 107: 14235–14240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bousquet M, Harris MH, Zhou B, Lodish HF . MicroRNA miR-125b causes leukemia. Proc Natl Acad Sci USA 2010; 107: 21558–21563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC . Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem 2007; 282: 1479–1486.

    Article  CAS  PubMed  Google Scholar 

  30. Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008; 14: 2690–2695.

    Article  CAS  PubMed  Google Scholar 

  31. Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007; 297: 1901–1908.

    Article  CAS  PubMed  Google Scholar 

  32. Klusmann JH, Li Z, Böhmer K, Kremens B, Vormoor J, Dworzak M et al. miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev 2010; 24: 478–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J, Akasaka T, Kato N et al. TEμ/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia 2011; 25: 1849–1856.

    Article  CAS  PubMed  Google Scholar 

  34. Webb CF, Smith EA, Medina KL, Allred L, Kim D, Harriss J et al. Expression of bright at two distinct stages of B lymphocyte development. J Immunol 1998; 160: 4747–4754.

    CAS  PubMed  Google Scholar 

  35. Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF . The transcription factor, Bright, is not expressed in all human B lymphocyte subpopulations. Cell Immunol 2004; 228: 42–53.

    Article  CAS  PubMed  Google Scholar 

  36. Gururajan M, Haga CL, Das S, Leu CM, Hodson D, Josson S et al. MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int Immunol 2010; 22: 583–592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schotte D, De Menezes RX, Moqadam FA, Khankahdani LM, Lange-Turenhout E, Chen C et al. MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica 2011; 96: 703–711.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the excellent support of the Nice-Sophia Antipolis Functional Genomics Platform for microarray processing. This work was supported by the Fondation pour la Recherche Médicale, a Carl-Duisberg scholarship from the Bayer Science and Education Foundation, the Institut National du Cancer, the Association pour la Recherche sur le Cancer (ARC), the CITTIL program and the Institut Universitaire de France.

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Author notes

  1. M P Puissegur and R Eichner: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, U1037, Centre de Recherches en Cancérologie de Toulouse, 31300 Toulouse, France,

    M P Puissegur, R Eichner, C Quelen, E Coyaud, C Broccardo, M Bousquet & P Brousset

  2. Université Paul Sabatier, Toulouse, France

    M P Puissegur, R Eichner, C Quelen, E Coyaud, C Broccardo, M Bousquet & P Brousset

  3. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR6097, Sophia Antipolis, France

    B Mari & K Lebrigand

  4. Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris 6, France

    F Nguyen-Khac

  5. INSERM U872, UPMC, Paris 6, France

    F Nguyen-Khac

  6. Département de Pathologie, Centre Hospitalier Universitaire Purpan, Toulouse, France

    P Brousset

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  1. M P Puissegur
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Correspondence to P Brousset.

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Author contributions

MPP, RE, CC and EC performed the experiments, BM, KL, CB and MB helped design experiments and interpret results, FNK provided patients’ samples. MPP, RE and PB designed the study and wrote the manuscript.

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Puissegur, M., Eichner, R., Quelen, C. et al. B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells. Leukemia 26, 2224–2232 (2012). https://doi.org/10.1038/leu.2012.95

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