Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia.

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias.

[1]  Bob Löwenberg,et al.  MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. , 2008, Blood.

[2]  Torsten Haferlach,et al.  Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin , 2008, Proceedings of the National Academy of Sciences.

[3]  Zhen-yi Wang,et al.  Acute promyelocytic leukemia: from highly fatal to highly curable. , 2008, Blood.

[4]  G. Behre,et al.  Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip. , 2008, Blood.

[5]  D. Tenen,et al.  Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha. , 2008, Blood.

[6]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[7]  J. Lieberman,et al.  let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells , 2007, Cell.

[8]  B. Frey,et al.  Using expression profiling data to identify human microRNA targets , 2007, Nature Methods.

[9]  F. Lo‐Coco,et al.  Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. , 2007, Cancer cell.

[10]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[11]  A. Armugam,et al.  MicroRNAs as therapeutic targets in human diseases , 2007, Expert opinion on therapeutic targets.

[12]  R. Nasr,et al.  RXR is an essential component of the oncogenic PML/RARA complex in vivo. , 2007, Cancer cell.

[13]  C. Croce,et al.  MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia , 2007, Oncogene.

[14]  Shaun Mahony,et al.  Regulatory conservation of protein coding and microRNA genes in vertebrates: lessons from the opossum genome , 2007, Genome biology.

[15]  L. Manchon,et al.  Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. , 2007, Blood.

[16]  Yoko Fukuda,et al.  An Evolutionarily Conserved Mechanism for MicroRNA-223 Expression Revealed by MicroRNA Gene Profiling , 2007, Cell.

[17]  T Chaplin,et al.  MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis , 2007, Leukemia.

[18]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[19]  Zhao-yue Wang,et al.  [The fibrinolytic activity in leukemic cell lines and its alteration on all-trans retinoic acid treatment]. , 2006, Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi.

[20]  Jin-Wu Nam,et al.  Genomics of microRNA. , 2006, Trends in genetics : TIG.

[21]  Alessandro Fatica,et al.  A Minicircuitry Comprised of MicroRNA-223 and Transcription Factors NFI-A and C/EBPα Regulates Human Granulopoiesis , 2005, Cell.

[22]  K. Livak,et al.  Real-time quantification of microRNAs by stem–loop RT–PCR , 2005, Nucleic acids research.

[23]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[24]  Charles Auffray,et al.  Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Graf,et al.  High expression of urokinase plasminogen activator receptor (UPA‐R) in acute myeloid leukemia (AML) is associated with worse prognosis , 2005, American journal of hematology.

[26]  A. Sandelin,et al.  Prediction of nuclear hormone receptor response elements. , 2005, Molecular endocrinology.

[27]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[28]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[29]  H. de Thé,et al.  PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation , 2004, The Journal of experimental medicine.

[30]  J. Bastien,et al.  Nuclear retinoid receptors and the transcription of retinoid-target genes. , 2004, Gene.

[31]  M. Lanotte,et al.  Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation , 2004, Leukemia.

[32]  S. Aref,et al.  Urokinase Plasminogen Activator Receptor and Soluble Matrix Metalloproteinase-9 in Acute Myeloid Leukemia Patients: A Possible Relation to Disease Invasion , 2003, Hematology.

[33]  J. She,et al.  Gene expression profiling during all-trans retinoic acid-induced cell differentiation of acute promyelocytic leukemia cells. , 2003, The Journal of molecular diagnostics : JMD.

[34]  V. Kim,et al.  The nuclear RNase III Drosha initiates microRNA processing , 2003, Nature.

[35]  Ki-Hwan Lee,et al.  Differential gene expression in retinoic acid-induced differentiation of acute promyelocytic leukemia cells, NB4 and HL-60 cells. , 2002, Biochemical and biophysical research communications.

[36]  S. Chevret,et al.  In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome. , 2001, Blood.

[37]  P. Knoepfler,et al.  HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation , 2001, Oncogene.

[38]  M. Lanotte,et al.  A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities , 2000, Leukemia.

[39]  C. Meijer,et al.  The role of Homeobox genes in normal hematopoiesis and hematological malignancies , 1999, Leukemia.

[40]  S. Mustjoki,et al.  Interferons and retinoids enhance and dexamethasone suppresses urokinase-mediated plasminogen activation in promyelocytic leukemia cells , 1998, Leukemia.

[41]  B. Hoffman,et al.  Lineage-specific regulation of hematopoiesis by HOX-B8 (HOX-2.4): inhibition of granulocytic differentiation and potentiation of monocytic differentiation. , 1997, Blood.

[42]  M. Lanotte,et al.  Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Vaheri,et al.  Induction of differentiation of promyelocytic NB4 cells by retinoic acid is associated with rapid increase in urokinase activity subsequently downregulated by production of inhibitors. , 1994, Blood.

[44]  Christine Chomienne,et al.  The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR , 1991, Cell.

[45]  R Berger,et al.  NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). , 1991, Blood.

[46]  H. Stunnenberg,et al.  Identification of a retinoic acid responsive element in the retinoic acid receptor & beta;gene , 1990, Nature.

[47]  W. Hiddemann,et al.  Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia. , 2008, Blood.

[48]  P. Choong,et al.  The urokinase plasminogen activator receptor as a gene therapy target for cancer. , 2007, Trends in biotechnology.

[49]  T. Naoe,et al.  In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. , 1996, Blood.

[50]  Najman,et al.  NB 4 , a Maturation Inducible Cell Line With t ( 15 ; 17 ) Marker Isolated From a Human Acute Promyelocytic Leukemia ( M 3 ) , 2022 .