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Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia

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Abstract

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

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References

  1. Artavanis-Tsakonas S, Rand MD, Lake RJ . Notch signaling: cell fate control and signal integration in development. Science 1999; 284: 770–776.

    Article  CAS  Google Scholar 

  2. Radtke F, Wilson A, Mancini SJ, MacDonald HR . Notch regulation of lymphocyte development and function. Nat Immunol 2004; 5: 247–253.

    Article  CAS  Google Scholar 

  3. Maillard I, Fang T, Pear WS . Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 2005; 23: 945–974.

    Article  CAS  Google Scholar 

  4. Screpanti I, Bellavia D, Campese AF, Frati L, Gulino A . Notch, a unifying target in T-cell acute lymphoblastic leukemia? Trends Mol Med 2003; 9: 30–35.

    Article  CAS  Google Scholar 

  5. Aster JC . Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int J Hematol 2005; 82: 295–301.

    Article  CAS  Google Scholar 

  6. Grabher C, von Boehmer H, Look AT . Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6: 347–359.

    Article  CAS  Google Scholar 

  7. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183: 2283–2291.

    Article  CAS  Google Scholar 

  8. Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A et al. Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J 2000; 19: 3337–3348.

    Article  CAS  Google Scholar 

  9. Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.

    Article  CAS  Google Scholar 

  10. Mansour MR, Linch DC, Foroni L, Goldstone AH, Gale RE . High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia 2006; 20: 537–539.

    Article  CAS  Google Scholar 

  11. Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci USA 2002; 99: 3788–3793.

    Article  CAS  Google Scholar 

  12. Espinosa L, Cathelin S, D'Altri T, Trimarchi T, Statnikov A, Guiu J et al. The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 2010; 18: 268–281.

    Article  CAS  Google Scholar 

  13. Vacca A, Felli MP, Palermo R, Di Mario G, Calce A, Di Giovine M et al. Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia. EMBO J 2006; 25: 1000–1008.

    Article  CAS  Google Scholar 

  14. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F et al. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 2007; 13: 70–77.

    Article  CAS  Google Scholar 

  15. Felli MP, Vacca A, Calce A, Bellavia D, Campese AF, Grillo R et al. PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene 2005; 24: 992–1000.

    Article  CAS  Google Scholar 

  16. Chen CZ, Li L, Lodish HF, Bartel DP . MicroRNAs modulate hematopoietic lineage differentiation. Science 2004; 303: 83–86.

    Article  CAS  Google Scholar 

  17. Esquela-Kerscher A, Slack FJ . Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–269.

    Article  CAS  Google Scholar 

  18. Schotte D, Pieters R, Den Boer ML . MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia 2012; 26: 1–12.

    Article  CAS  Google Scholar 

  19. Agirre X, Martinez-Climent JA, Odero MD, Prosper F . Epigenetic regulation of miRNA genes in acute leukemia. Leukemia 2012; 26: 395–403.

    Article  CAS  Google Scholar 

  20. 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  Google Scholar 

  21. Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS et al. MicroRNA profiling in human medulloblastoma. Int J Cancer 2009; 124: 568–577.

    Article  CAS  Google Scholar 

  22. De Smaele E, Ferretti E, Gulino A . MicroRNAs as biomarkers for CNS cancer and other disorders. Brain Res 2010; 1338: 100–111.

    Article  CAS  Google Scholar 

  23. Wang Z, Li Y, Kong D, Ahmad A, Banerjee S, Sarkar FH . Cross-talk between miRNA and Notch signaling pathways in tumor development and progression. Cancer Lett 2010; 292: 141–148.

    Article  CAS  Google Scholar 

  24. Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009; 69: 7569–7576.

    Article  CAS  Google Scholar 

  25. Li X, Sanda T, Look AT, Novina CD, von Boehmer H . Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med 2011; 208: 663–675.

    Article  CAS  Google Scholar 

  26. Kuang W, Tan J, Duan Y, Duan J, Wang W, Jin F et al. Cyclic stretch induced miR-146a upregulation delays C2C12 myogenic differentiation through inhibition of Numb. Biochem Biophys Res Commun 2009; 378: 259–263.

    Article  CAS  Google Scholar 

  27. Ghisi M, Corradin A, Basso K, Frasson C, Serafin V, Mukherjee S et al. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150. Blood 2011; 117: 7053–7062.

    Article  CAS  Google Scholar 

  28. Song G, Zhang Y, Wang L . MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation. J Biol Chem 2009; 284: 31921–31927.

    Article  CAS  Google Scholar 

  29. Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K et al. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol 2010; 12: 372–379.

    Article  CAS  Google Scholar 

  30. Palermo R, Checquolo S, Giovenco A, Grazioli P, Kumar V, Campese AF et al. Acetylation controls Notch3 stability and function in T-cell leukemia. Oncogene 2012; 31: 3807–3817.

    Article  CAS  Google Scholar 

  31. Talora C, Cialfi S, Oliviero C, Palermo R, Pascucci M, Frati L et al. Cross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesis. Blood 2006; 107: 3313–3320.

    Article  CAS  Google Scholar 

  32. Talora C, Sgroi DC, Crum CP, Dotto GP . Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 2002; 16: 2252–2263.

    Article  CAS  Google Scholar 

  33. Bellavia D, Mecarozzi M, Campese AF, Grazioli P, Talora C, Frati L et al. Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. EMBO J 2007; 26: 1670–1680.

    Article  CAS  Google Scholar 

  34. Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M et al. Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. J Immunol 2011; 186: 6199–6206.

    Article  CAS  Google Scholar 

  35. Canettieri G, Santaguida MG, Antonucci L, Della Guardia M, Franchi A, Coni S et al. CCAAT/enhancer-binding proteins are key regulators of human type two deiodinase expression in a placenta cell line. Endocrinology 2012; 153: 4030–4038.

    Article  CAS  Google Scholar 

  36. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A . Signalling downstream of activated mammalian Notch. Nature 1995; 377: 355–358.

    Article  CAS  Google Scholar 

  37. Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M et al. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma. EMBO Rep 2003; 4: 1067–1072.

    Article  CAS  Google Scholar 

  38. Primi D, Clynes RA, Jouvin-Marche E, Marolleau JP, Barbier E, Cazenave PA et al. Rearrangement and expression of T cell receptor and immunoglobulin loci in immortalized CD4−CD8− T cell lines. Eur J Immunol 1988; 18: 1101–1109.

    Article  CAS  Google Scholar 

  39. Mavrakis KJ, Van Der Meulen J, Wolfe AL, Liu X, Mets E, Taghon T et al. A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet 2011; 43: 673–678.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 2007; 129: 617–631.

    Article  CAS  Google Scholar 

  42. He KL, Ting AT . Essential role for IKKgamma/NEMO in TCR-induced IL-2 expression in Jurkat T cells. Eur J Immunol 2003; 33: 1917–1924.

    Article  CAS  Google Scholar 

  43. Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med 2013; 210: 1545–1557.

    Article  CAS  Google Scholar 

  44. Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F, Satyal S et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 2013; 28: 278–288.

    Article  Google Scholar 

  45. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 2007; 204: 1813–1824.

    Article  CAS  Google Scholar 

  46. Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH et al. Tumor suppressor functions of FBW7 in cancer development and progression. FEBS Lett 2012; 586: 1409–1418.

    Article  CAS  Google Scholar 

  47. Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U . The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J Biol Chem 2001; 276: 35847–35853.

    Article  CAS  Google Scholar 

  48. Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 2004; 23: 2116–2125.

    Article  CAS  Google Scholar 

  49. Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI . Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 2001; 413: 316–322.

    Article  CAS  Google Scholar 

  50. Gusscott S, Kuchenbauer F, Humphries RK, Weng AP . Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL. Leuk Res 2012; 36: 905–911.

    Article  CAS  Google Scholar 

  51. Medyouf H, Gao X, Armstrong F, Gusscott S, Liu Q, Gedman AL et al. Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss. Blood 2010; 115: 1175–1184.

    Article  CAS  Google Scholar 

  52. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66: 649–661.

    Article  CAS  Google Scholar 

  53. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 2005; 19: 1841–1843.

    Article  CAS  Google Scholar 

  54. Ferrando A . NOTCH mutations as prognostic markers in T-ALL. Leukemia 2010; 24: 2003–2004.

    Article  CAS  Google Scholar 

  55. Ferrando AA, Look AT . Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin Hematol 2003; 40: 274–280.

    Article  CAS  Google Scholar 

  56. Correia NC, Durinck K, Leite AP, Ongenaert M, Rondou P, Speleman F et al. Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia. Leukemia 2013; 27: 1603–1606.

    Article  CAS  Google Scholar 

  57. Wang Z, Fukushima H, Gao D, Inuzuka H, Wan L, Lau AW et al. The two faces of FBW7 in cancer drug resistance. BioEssays 2011; 33: 851–859.

    Article  CAS  Google Scholar 

  58. Park MJ, Taki T, Oda M, Watanabe T, Yumura-Yagi K, Kobayashi R et al. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol 2009; 145: 198–206.

    Article  CAS  Google Scholar 

  59. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 2007; 204: 1825–1835.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Sonia Minuzzo for help in establishing T-ALL xenografts. This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Ministry of University and Research (MIUR), FIRB and PRIN Programs, the European Union (FP7-MC-ITN 215761-NotchIT).

Author contributions

VK and RP designed and performed experiments, analyzed data and wrote the paper; AFC, LT, EM and GT performed experiments; SC and DB analyzed data; SI, AA, CT, EF, AG, AV and IS designed experiments, analyzed data and wrote the paper.

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Correspondence to I Screpanti.

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Kumar, V., Palermo, R., Talora, C. et al. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia 28, 2324–2335 (2014). https://doi.org/10.1038/leu.2014.133

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