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Emerging Role for MicroRNAs in Acute Promyelocytic Leukemia

  • C. Nervi
  • F. Fazi
  • A. Rosa
  • A. Fatica
  • I. Bozzoni
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 313)

Abstract

Hematopoiesis is highly controlled by lineage-specific transcription factors that, by interacting with specific DNA sequences, directly activate or repress specific gene expression. These transcription factors have been found mutated or altered by chromosomal translocations associated with leukemias, indicating their role in the pathogenesis of these malignancies. The post-genomic era, however, has shown that transcription factors are not the only key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, posttranslational modifications of histones, remodeling of nucleosomes, and expression of small regulatory RNAs all contribute to the regulation of gene expression and determination of cell and tissue specificity. Deregulation of these epigenetic mechanisms cooperates with genetic alterations to the establishment and progression of tumors. MicroRNAs (miRNAs) are negative regulators of the expression of genes involved in development, differentiation, proliferation, and apoptosis. Their expression appears to be tissue-specific and highly regulated according to the cell’s developmental lineage and stage. Interestingly, miRNAs expressed in hematopoietic cells have been found mutated or altered by chromosomal translocations associated with leukemias. The expression levels of a specific miR-223 correlate with the differentiation fate of myeloid precursors. The activation of both pathways of transcriptional regulation by the myeloid lineage-specific transcription factor C/EBPα (CCAAT/enhancer-binding protein-α), and posttranscriptional regulation by miR-223 appears essential for granulocytic differentiation and clinical response of acute promyelocytic leukemia (APL) blasts to all-trans retinoic acid (ATRA). Together, this evidence underlies transcription factors, chromatin remodeling, and miRNAs as ultimate determinants for the correct organization of cell type-specific gene arrays and hematopoietic differentiation, therefore providing new targets for the diagnosis and treatment of leukemias.

Keywords

Acute Myeloid Leukemia Retinoic Acid Treatment Myeloid Cell Line Hematopoietic Differentiation Granulocytic Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Ambros V (2004) The function of animal miRNAs. Nature 431:350–355PubMedCrossRefGoogle Scholar
  2. Bartell DP (2004) MicroRNAs: genomics, biogenesis, mechanism and function. Cell 116:281–297CrossRefGoogle Scholar
  3. Caldas C, Brenton JD (2005) Sizing up miRNAs as cancer genes. Nat Med 11:712–714PubMedCrossRefGoogle Scholar
  4. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801PubMedCrossRefGoogle Scholar
  5. Chen CZ (2005) MicroRNAs as oncogenes and tumor suppressors. N Engl J Med 353:1768–1771PubMedCrossRefGoogle Scholar
  6. Chen CZ, Li L, Lodish HF, Bartell DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86PubMedCrossRefGoogle Scholar
  7. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082PubMedCrossRefGoogle Scholar
  8. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I (2005) A minicircuitry comprising microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell 123:819–831PubMedCrossRefGoogle Scholar
  9. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C (2005) MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via Kit receptor downmodulation. Proc Natl Acad Sci U S A 102:18081–18086PubMedCrossRefGoogle Scholar
  10. Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pelicci PG, Lo Coco F, Nervi C (2001) Histone deacetylase targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2–7PubMedGoogle Scholar
  11. Filipowicz W (2005) RNAi: the nuts and bolts of the RISC machine. Cell 122:17–20PubMedCrossRefGoogle Scholar
  12. Garlatti M, Tchesnokov V, Daheshia M, Feilleux-Duche S, Hanoune J, Aggerbeck M, Barouki R (1993) CCAAT/enhancer-binding protein-related proteins bind to the unusual promoter of the aspartate aminotransferase housekeeping gene. J Biol Chem 268:6567–6574PubMedGoogle Scholar
  13. Gronostajski RM (2000) Roles of the NF1/CTF gene family in transcription and development. Gene 249:31–45PubMedCrossRefGoogle Scholar
  14. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500PubMedCrossRefGoogle Scholar
  15. Lee YS, Nakahara K, Pham JW, Kim K, He Z, Sontheimer EJ, Carthew RW (2004) Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117:69–81PubMedCrossRefGoogle Scholar
  16. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20PubMedCrossRefGoogle Scholar
  17. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedCrossRefGoogle Scholar
  18. Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431:343–349PubMedCrossRefGoogle Scholar
  19. Meisterernst M, Gander I, Rogge L, Winnacker EL (1988) A quantitative analysis of nuclear factor I/DNA interactions. Nucleic Acids Res 16:4419–4435PubMedCrossRefGoogle Scholar
  20. Melnick A, Licht JD (1999) Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93:3167–3215PubMedGoogle Scholar
  21. Okamura K, Ishizuka A, Siomi H, Siomi MC (2004) Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes Dev 18:1655–1666PubMedCrossRefGoogle Scholar
  22. Pasquinelli AE, Hunter S, Bracht J (2005) MicroRNAs: a developing story. Curr Opin Genet Dev 15:200–205PubMedCrossRefGoogle Scholar
  23. Rabbitts TH (1994) Chromosomal translocations in human cancer. Nature 372:143–149PubMedCrossRefGoogle Scholar
  24. Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG (1998) CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 18:4301–4314PubMedGoogle Scholar
  25. Salomoni P, Pandolfi PP (2000) Transcriptional regulation of cellular transformation. Nat Med 6:742–744PubMedCrossRefGoogle Scholar
  26. Sanz MA, Tallman MS, Lo-Coco F (2005) Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 105:3019–3025PubMedCrossRefGoogle Scholar
  27. Shao W, Benedetti L, Lamph WW, Nervi C, Miller WHJ (1997) A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PMLRARα mutation. Blood 89:4282–4289PubMedGoogle Scholar
  28. Sontheimer EJ, Carthew RW (2005) Silence from within: endogenous siRNAs and miRNAs. Cell 122:9–12PubMedCrossRefGoogle Scholar
  29. Tenen DG (2003) Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 3:89–101PubMedCrossRefGoogle Scholar
  30. Tenen DG, Hromas R, Licht JD, Zhang DE (1997) Transcription factors, normal myeloid development, and leukemia. Blood 90:489–519PubMedGoogle Scholar
  31. Truong BT, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N, Koeffler HP, Nakajima H, Tenen DG, Kogan SC (2003) CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101:1141–1148PubMedCrossRefGoogle Scholar
  32. Tsai S, Bartelmez S, Heyman RA, Damm K, Evans RM, Collins SJ (1992) A mutated retinoic acid receptor-α exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line. Genes Dev 6:2258–2269PubMedGoogle Scholar
  33. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG (1997) Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A 94:569–574PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • C. Nervi
    • 1
  • F. Fazi
    • 1
  • A. Rosa
    • 2
  • A. Fatica
    • 2
  • I. Bozzoni
    • 2
  1. 1.Department of Histology and Medical EmbryologyUniversity of Rome “La Sapienza” and San Raffaele Bio-medical Park FoundationRomeItaly
  2. 2.Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology and I.B.P.M.University of Rome “La Sapienza”RomeItaly

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