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.

A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. A small set of miRNAs is differentially expressed in hematopoietic cells and seemingly has an important role in granulopoiesis and lineage differentiation. In this study, we analysed, using a quantitative real-time PCR approach, the expression of 12 granulocytic differentiation signature miRNAs in a cohort of acute promyelocytic leukemia (APL) patients. We found nine miRNAs overexpressed and three miRNAs (miR-107, -342 and let-7c) downregulated in APL blasts as compared with normal promyelocytes differentiated in vitro from CD34+ progenitors. Patients successfully treated with all-trans-retinoic acid (ATRA) and chemotherapy showed downregulation of miR-181b and upregulation of miR-15b, -16, -107, -223, -342 and let-7c. We further investigated whether the APL-associated oncogene, promyelocytic leukemia gene (PML)/retinoic acid receptor α (RARα), might be involved in the transcriptional repression of miR-107, -342 and let-7c. We found that PML/RARα binds the regulatory sequences of the intragenic miR-342 and let-7c. In addition, we observed, in response to ATRA, the release of PML/RARα paralleled by their transcriptional activation, together with their host genes, EVL and C21orf34α. In conclusion, we show that a small subset of miRNAs is differentially expressed in APL and modulated by ATRA-based treatment.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Abramovich C, Humphries RK . (2005). Hox regulation of normal and leukemic hematopoietic stem cells. Curr Opin Hematol 12: 210–216.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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 

  • De Marchis ML, Ballarino M, Salvatori B, Puzzolo MC, Bozzoni I, Fatica A . (2009). A new molecular network comprising PU.1, interferon regulatory factor proteins and miR-342 stimulates ATRA-mediated granulocytic differentiation of acute promyelocytic leukemia cells. Leukemia 23: 856–862.

    Article  CAS  PubMed  Google Scholar 

  • Diaz-Blanco E, Bruns I, Neumann F, Fischer JC, Graef T, Rosskopf M et al. (2007). Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 21: 494–504.

    Article  CAS  PubMed  Google Scholar 

  • 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: 1095–1105.

    Article  CAS  PubMed  Google Scholar 

  • Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C et al. (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 

  • Fontana L, Pelosi E, Greco P, Racanicchi S, Testa U, Liuzzi F et al. (2007). MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat Cell Biol 9: 775–787.

    Article  CAS  PubMed  Google Scholar 

  • Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A et al. (2007). MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 26: 4148–4157.

    Article  CAS  PubMed  Google Scholar 

  • Grady WM, Parkin RK, Mitchell PS, Lee JH, Kim Y-H, Tsuchiya KD et al. (2008). Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene 27: 3880–3888.

    Article  CAS  PubMed  Google Scholar 

  • Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M et al. (1993). The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74: 423–431.

    Article  CAS  PubMed  Google Scholar 

  • Johnson SM, Grosshans 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 

  • Kim YK, Kim VN . (2007). Processing of intronic microRNAs. EMBO J 26: 775–783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar AR, Quanzhi L, Hudson WA, Chen W, Sam T, Yao Q et al. (2009). A role for MEIS1 in MLL-fusion gene leukemia. Blood 113: 1756–1758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mainardi S, Pelosi A, Palescandolo E, Riccioni R, Fontemaggi G, Diverio D et al. (2007). DeltaN-p73 is a transcriptional target of the PML/RARalpha oncogene in myeloid differentiation. Cell Death Diff 14: 1968–1971.

    Article  CAS  Google Scholar 

  • Mallardo M, Poltronieri P, D'Urso OF . (2008). Non-protein coding RNA biomarkers and differential expression in cancers: a review. J Exp Clin Cancer Res 27: 19.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C et al. (1997). Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90: 1014–1021.

    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 

  • Meltzer PS . (2005). Cancer genomics: small RNAs with big impacts. Nature 435: 745–746.

    Article  CAS  PubMed  Google Scholar 

  • Pasquinelli AE, Hunter S, Bracht J . (2005). MicroRNAs: a developing story. Curr Opin Genet Dev 15: 200–205.

    Article  CAS  PubMed  Google Scholar 

  • Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P et al. (2008). Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res 6: 663–673.

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A . (2004). Identification of mammalian microRNA host genes and transcription units. Genome Res 14: 1902–1910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenauer A, Raelson JV, Nervi C, Eydoux P, DeBlasio A, Miller WH . (1996). Alterations in expression, binding to ligand and DNA, and transcriptional activity of rearranged and wild-type retinoid receptors in retinoid-resistant acute promyelocytic leukaemia cell lines. Blood 88: 2671–2682.

    CAS  PubMed  Google Scholar 

  • Saumet A, Vetter G, Bouttier B, Casamar-Portales E, Wasserman WW, Maurin T et al. (2009). Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood 113: 412–421.

    Article  CAS  PubMed  Google Scholar 

  • Tallman MS, Nabhan C, Feusner JH, Rowe JM . (2002). Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 99: 759–767.

    Article  CAS  PubMed  Google Scholar 

  • Testa U, Fossati C, Samoggia P, Masciulli R, Mariani G, Hassan HJ et al. (1996). Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors. Blood 88: 3391–3406.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr WH Miller Jr for kindly providing the NB4 sub-clone MR2 and Dr I Sperduti for his help on statistical analysis. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Salute-Italy and European Community (Eu Active p53 Consortium).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to M Levrero or M G Rizzo.

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

Careccia, S., Mainardi, S., Pelosi, A. et al. A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes. Oncogene 28, 4034–4040 (2009). https://doi.org/10.1038/onc.2009.255

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.255

Keywords

This article is cited by

Search

Quick links