Molecular and Cellular Biochemistry

, Volume 340, Issue 1–2, pp 97–106 | Cite as

Potential tumor suppressive function of miR-196b in B-cell lineage acute lymphoblastic leukemia

  • Suman Bhatia
  • Deepak KaulEmail author
  • Neelam Varma


Keeping in view the fact that genes coding microRNAs (miRNAs) have been found to be localized in chromosomal regions susceptible to genetic translocations, this study was addressed to identify and characterize the miRNAs that are present near/within the regions involved in genetic translocations characteristic of B-cell acute lymphoblastic leukemia (B-cell ALL). Out of six such identified miRNAs miR-196b was not only found to be significantly down-regulated in both EB-3 cell line as well as B-cell ALL patients as compared to that found in the corresponding controls, but also had the inherent capacity to down-regulate the highly expressed c-myc gene, a consequence of genetic translocation characteristic of EB-3 cells at both transcriptional and translational level. This phenomenon was in conformity with the observed reciprocal relationship between the expressed genes coding for miR-196b and c-myc in B-cells derived from ALL patients as well as c-myc gene was found to be a putative target of miR-196b as predicted by bioinformatic algorithms. Also down-regulation of c-myc gene was accompanied by decreased expressions of c-myc effector genes coding for hTERT, Bcl-2, and AATF. Based upon these results, we propose for the first time that miR-196b has the inherent capacity to down-regulate the overamplified c-myc gene recognized as a common pathognomonic feature leading to cancer in general and B-cell ALL in particular. Hence miR-196b can be assigned with the tumor suppressor function and can be of therapeutic importance in paving the way toward the treatment of B-cell ALL.


miRNAs miR-196b Tumor suppressor c-myc Translocations B-cell acute lymphoblastic leukemia 



The study is funded by Department of Biotechnology, Govt. of India, New Delhi.


  1. 1.
    Kent OA, Mendell JT (2006) A small piece in cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25:6188–6196CrossRefPubMedGoogle Scholar
  2. 2.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefPubMedGoogle Scholar
  3. 3.
    Wightman B, Ha I, Ruvkun G (2004) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediator temporal pattern formation in C. elegans. Cell 75:855–862CrossRefGoogle Scholar
  4. 4.
    Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355CrossRefPubMedGoogle Scholar
  5. 5.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedGoogle Scholar
  6. 6.
    Carleton M, Cleary MA, Linsley PS (2007) MicroRNAs and cell cycle regulation. Cell Cycle 6:2127–2132PubMedGoogle Scholar
  7. 7.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zuop S, Noch E, Aldler H, Rattan S, Keating M, Rai K et al (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529CrossRefPubMedGoogle Scholar
  8. 8.
    Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39:167–169CrossRefPubMedGoogle Scholar
  9. 9.
    Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101:2999–3004CrossRefPubMedGoogle Scholar
  10. 10.
    Calin GA, Croce CM (2006) MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene 25:6202–6210CrossRefPubMedGoogle Scholar
  11. 11.
    McManus MT (2003) MicroRNAs and cancer. Semin Cancer Biol 13:253–258CrossRefPubMedGoogle Scholar
  12. 12.
    Wijhoven BPL, Michael MZ, Watson DI (2007) MicroRNAs and cancer. Br J Sur 94:23–30CrossRefGoogle Scholar
  13. 13.
    Gartel AL, Kandel EU (2008) miRNAs: little known mediators of oncogenesis. Semin Cancer Biol 18:103–110CrossRefPubMedGoogle Scholar
  14. 14.
    Kaul D (1998) Receptor-CK and leukemogenesis. Leuk Res 22:562–564Google Scholar
  15. 15.
    Fabbri M, Garzon R, Andreeff M, Kantarjian HM, Garcia-Manero G, Calin GA (2008) MicroRNAs and noncoding RNAs in hematological malignancies:molecular, clinical and therapeutic implications. Leukemia 22:1095–1105CrossRefPubMedGoogle Scholar
  16. 16.
    Schickel R, Boyerinas B, Park SM, Peter ME (2008) MicroRNAs: key players in immune system, differentiation, tumorigenesis and cell death. Oncogene 27:5959–5974CrossRefPubMedGoogle Scholar
  17. 17.
    Pui CH, Evans WE (1998) Acute lymphoblastic leukemia. N Engl J Med 339:605–615CrossRefPubMedGoogle Scholar
  18. 18.
    Pui CH, Relling MV, Downing JR (2004) Acute lymphoblastic leukemia. N Engl J Med 350:1535–1548CrossRefPubMedGoogle Scholar
  19. 19.
    Hecht JL, Aster JC (2000) Molecular biology of Burkitt’s lymphoma. J Clin Oncol 18:3707–3721PubMedGoogle Scholar
  20. 20.
    Kaul D, Khanna A, Suman (2006) Evidence and nature of a novel miRNA encoded by HIV-1. Proc Indian Natl Sci Acad 72:91–95Google Scholar
  21. 21.
    Chomczynski P, Sacchi N (1987) Single step method of RNA isolation by acid guanidium thiocynate phenol chloroform extraction. Anal Biochem 162:156–159CrossRefPubMedGoogle Scholar
  22. 22.
    John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS (2004) Human MicroRNA targets. PLoS Biol 2:e363CrossRefPubMedGoogle Scholar
  23. 23.
    Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP, Krueger LJ (2007) MicroRNA Let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67:9762–9770CrossRefPubMedGoogle Scholar
  24. 24.
    Cimmino A, Calin GA, Fabbri M, Iorio M, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949CrossRefPubMedGoogle Scholar
  25. 25.
    Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647CrossRefPubMedGoogle Scholar
  26. 26.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843CrossRefPubMedGoogle Scholar
  27. 27.
    Wiemer EAC (2007) The role of microRNAs in cancer: no small matter. Eur J Cancer 43:1529–1544CrossRefPubMedGoogle Scholar
  28. 28.
    Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66:407–425CrossRefPubMedGoogle Scholar
  29. 29.
    Hu BT, Insel RA (1999) Up-regulation of telomerase in human B lymphocytes occurs independently of cellular proliferation and with expression of the telomerase catalytic subunit. Eur J Immunol 29:3745–3753CrossRefPubMedGoogle Scholar
  30. 30.
    Horikawa I, Cable PL, Afshari C et al (1999) Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res 59:826–830PubMedGoogle Scholar
  31. 31.
    Wang J, Liu X, Jiang W et al (2000) Telomerase activity and expression of the telomerase catalytic subunit gene in non-small cell lung cancer: correlation with decreased apoptosis and clinical prognosis. Chin Med J 113:985–990PubMedGoogle Scholar
  32. 32.
    Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (2003) Genomic targets of the human c-Myc protein. Genes Dev 17:1115–1129CrossRefPubMedGoogle Scholar
  33. 33.
    Kaul D, Mehrotra A (2007) Functional characterization of AATF transcriptome in human leukemic cells. Mol Cell Biochem 297:215–220CrossRefPubMedGoogle Scholar
  34. 34.
    Kaul D, Ahlawat A, Gupta SD (2009) HIV-1 genome-encoded hiv1-mir-H1 impairs cellular responses to infection. Mol Cell Biochem 323:143–148CrossRefPubMedGoogle Scholar
  35. 35.
    Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756CrossRefPubMedGoogle Scholar
  36. 36.
    Chang C, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas Tikhonenko A, Mendell JT (2008) Widespread microRNAs repression by Myc contributes to tumorigenesis. Nat Genet 40:43–50CrossRefPubMedGoogle Scholar
  37. 37.
    Schotte D, Chau JCK, Sylvester G, Liu G, Chen C, van der Velden VHJ, Broekhuis MJC, Peters TCJM, Pieters R, den Boer ML (2009) Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia. Leukemia 23:313–322CrossRefPubMedGoogle Scholar
  38. 38.
    Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ, Erfurth FE, Eaton K, Lu J, Grimes HL, Chen J, Rowley JD, Zeleznik-Le NJ (2009) Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113:3314–3322CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Molecular Biology Unit, Department of Experimental Medicine and BiotechnologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of HematologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

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