Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia

A Correction to this article was published on 11 May 2022

This article has been updated

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs of 19–25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time–polymerase chain reaction (qRT–PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-κB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NFB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.

This is a preview of subscription content, access via your institution

Access options

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Change history

References

  • Bartel DP . (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  • Bowen DT, Frew ME, Hills R, Gale RE, Weathley K, Groves M et al. (2005). RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 106: 2113–2119.

    Article  CAS  PubMed  Google Scholar 

  • Bruel A, Benoit G, De Nay D, Brown S, Lanotte M . (1995). Distinct apoptotic responses in maturation sensitive and resistant t (15; 17) acute promyelocytic leukemia NB4 cells. 9cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression. Leukemia 9: 1173–1184.

    CAS  PubMed  Google Scholar 

  • Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H et al. (2006). Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood 108: 1708–1715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cheng AM, Byrom MW, Shelton J, Ford LP . (2005). Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 33: 1290–1297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cimmino A, Calin GA, Muller F, Iorio M, Ferracin M, Shimitzu M et al. (2005). Mir-15a and miR-16-1 induced apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102: 13944–13949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dechend R, Hirano F, Lehmann K, Heissmayer V, Ansieau S, Wulczyn F et al. (1999). The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 18: 3316–3323.

    Article  CAS  PubMed  Google Scholar 

  • Dresios J, Aschrafi A, Owens GC, Vanderkilsh PW, Edelman GM, Mauro VP . (2005). Cold stress induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis. Proc Natl Acad Sci USA 102: 1865–1870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fazi F, Rosa A, Fatica A, Gelmetti V, Marchis ML, Nervi C et al. (2005). A mini-circuitry comprising microRNA-223 and transcription factors NFI-A and C/EBPa regulates human granulopoiesis. Cell 123: 819–831.

    Article  CAS  PubMed  Google Scholar 

  • John B, Enright J, Aravin A, Tuschl T, Sander C, Marks DS . (2004). Human microRNA targets. Plos biology 11: e363.

    Article  Google Scholar 

  • Johnson SM, Grosshands H, Shingara J, Byrom M, Jarvis R, Cheng A et al. (2005). Ras is regulated by the let-7 microRNA family. Cell 120: 635–647.

    Article  CAS  PubMed  Google Scholar 

  • Kel AE, Gossling E, Reuter I, Cheremushkin E, Kel-Margoulis OV, Wingender E . (2003). MATCH: a tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res 31: 3576–3579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolch W . (2005). Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 11: 827–837.

    Article  Google Scholar 

  • Kurland JF, Kodym R, Story MD, Spurgers KB, Mc Donnell TJ, Meyn RE . (2001). NF-kappaB1 (p50) homodimers contribute to transcription of the bcl-2 oncogene. J Biochem Chem 30: 45380–45386.

    Google Scholar 

  • Krek A, Grün D, Poy M, Wolf R, Rosenberg L, Epstein EJ et al. (2005). Combinatorial microRNA target predictions. Nat Genet 37: 495–500.

    Article  CAS  PubMed  Google Scholar 

  • Lewis BP, Shih IH, Jones-Rhoades MW, Bartel P, Burge CB . (2003). Prediction of mammalian microRNA targets. Cell 115: 787–798.

    Article  CAS  PubMed  Google Scholar 

  • Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M et al. (2004). An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci USA 101: 9740–9744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathieu J, Giraudier S, Lanotte M, Besancon F . (2005). Retinoic-induced activation of NF-kB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells. Oncogene 24: 7145–7155.

    Article  CAS  PubMed  Google Scholar 

  • Meani N, Minardi S, Licciulli S, Gelmetti V, Lo Coco F, Nervi C et al. (2005). Molecular signature of retinoic acid treatment in acute promyelocytic leukemia. Oncogene 24: 3358–3368.

    Article  CAS  PubMed  Google Scholar 

  • Melnick A, Licht JD . (1999). Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.

    CAS  PubMed  Google Scholar 

  • Mori N, Fujii M, Ikeda S, Yamada Y, Tomonaga M, Ballard DW et al. (1999). Constitutive activation of NF-κB in primary adult T-cell leukemia cells. Blood 93: 2360–2368.

    CAS  PubMed  Google Scholar 

  • Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, McDonald PE et al. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432: 226–230.

    Article  CAS  PubMed  Google Scholar 

  • Priel IP, Cai DH, Wang D, Kowalski J, Blackford A, Liu H . (2005). CCAAT/Enhancer binding protein α(EBPα) and C/EBPα myeloid oncoproteins induce Bcl-2 via interaction of their basic regions with nuclear factor-κB p50. Mol Cancer Reser 3: 585–596.

    Article  Google Scholar 

  • Tusher VG, Tibshirani R, Chu G . (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98: 5116–5121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Udalova IA, Richardson A, Denys A, Smith C, Ackerman H, Foxwell B et al. (2000). Functional consequences of a polymorphism affecting NF-κB p50-p50 binding to the TNF promoter region. Mol Cell Biol 20: 9113–9119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Cancer Institute/National Institutes of Health Grants, P01CA76259, P01CA16058 and P01CA81534 (CMC), P01 CA055164 and the Paul and Mary Haas Chair in Genetics (MA), Lauri Strauss Discovery grants awards (RG), Kimmel Foundation grants awards (GAC and RA) and CLL Global Research Foundation Grant (GAC). We thank Guido Marcucci for kindly providing us with NB4 cells and Dennis Guttridge for his generous support with many reagents used to characterize the NFB regulated miRNAs (The Ohio State University).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C M Croce.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garzon, R., Pichiorri, F., Palumbo, T. et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 26, 4148–4157 (2007). https://doi.org/10.1038/sj.onc.1210186

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210186

Keywords

This article is cited by

Search

Quick links