MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia.

Elevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In this study, we present evidence that MYB (v-myb myeloblastosis viral oncogene homolog) is overexpressed in a subset of B-CLL patients. MYB physically associates with the promoter of miR-155 host gene (MIR155HG, also known as BIC, B-cell integration cluster) and stimulates its transcription. This coincides with the hypermethylated histone H3K4 residue and spread hyperacetylation of H3K9 at MIR155HG promoter. Our data provide evidence of oncogenic activities of MYB in B-CLL that include its stimulatory role in MIR155HG transcription.

[1]  M. Lacey,et al.  MicroRNA-155 Is an Epstein-Barr Virus-Induced Gene That Modulates Epstein-Barr Virus-Regulated Gene Expression Pathways , 2008, Journal of Virology.

[2]  A. van den Berg,et al.  BIC and miR‐155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas , 2005, The Journal of pathology.

[3]  D. Halbert,et al.  T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. , 2002, Cellular immunology.

[4]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[5]  Stefano Volinia,et al.  Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[6]  V. Ambros.  microRNAs Tiny Regulators with Great Potential , 2001, Cell.

[7]  Robert G. Ramsay,et al.  MYB function in normal and cancer cells , 2008, Nature Reviews Cancer.

[8]  A. Feeney,et al.  Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. , 1996, The EMBO journal.

[9]  Š. Pospíšilová,et al.  MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes , 2009, Leukemia & lymphoma.

[10]  Achim Leutz,et al.  Histone H3 tail positioning and acetylation by the c-Myb but not the v-Myb DNA-binding SANT domain. , 2005, Genes & development.

[11]  H. Döhner,et al.  From pathogenesis to treatment of chronic lymphocytic leukaemia , 2010, Nature Reviews Cancer.

[12]  C. Croce,et al.  Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes. , 2009, Blood.

[13]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[14]  Erik Flemington,et al.  B-cell Receptor Activation Induces BIC/miR-155 Expression through a Conserved AP-1 Element* , 2008, Journal of Biological Chemistry.

[15]  A I Saeed,et al.  TM4: a free, open-source system for microarray data management and analysis. , 2003, BioTechniques.

[16]  A. Gewirtz,et al.  c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. , 2010, The Journal of clinical investigation.

[17]  W. Liang,et al.  9) TM4 Microarray Software Suite , 2006 .

[18]  S. Ness,et al.  Activities Transcriptional Forms of C-myb with Unique Alternative Rna Splicing Produces Multiple Supplemental Material , 2007 .

[19]  E. Morii,et al.  Latent membrane protein-1 of Epstein-Barr virus induces the expression of B-cell integration cluster, a precursor form of microRNA-155, in B lymphoma cell lines. , 2008, Biochemical and biophysical research communications.

[20]  Arndt Borkhardt,et al.  High expression of precursor microRNA‐155/BIC RNA in children with Burkitt lymphoma , 2004, Genes, chromosomes & cancer.

[21]  D. Allman,et al.  c-Myb Is Required for Pro-B Cell Differentiation1 , 2009, The Journal of Immunology.

[22]  Aadel A. Chaudhuri,et al.  Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder , 2008, The Journal of experimental medicine.

[23]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[24]  T. Langmann,et al.  Transcriptomic profiling identifies a PU.1 regulatory network in macrophages. , 2009, Biochemical and biophysical research communications.

[25]  Michael B. Stadler,et al.  Transcription factor site dependencies in human, mouse and rat genomes , 2009, BMC Bioinformatics.

[26]  A. van den Berg,et al.  miRNA analysis in B‐cell chronic lymphocytic leukaemia: proliferation centres characterized by low miR‐150 and high BIC/miR‐155 expression , 2008, The Journal of pathology.

[27]  Masaomi Kato,et al.  microRNAs: small molecules with big roles –C. elegans to human cancer , 2008, Biology of the cell.

[28]  A. van den Berg,et al.  High expression of B‐cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma , 2002, Genes, chromosomes & cancer.

[29]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[30]  A. Rossi,et al.  Epstein – Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NFi B pathway , 2008 .

[31]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Chris Sander,et al.  Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. , 2007, Blood.

[33]  Daniel G. Tenen,et al.  Transcription factors in myeloid development: balancing differentiation with transformation , 2007, Nature Reviews Immunology.

[34]  D. Hilton,et al.  Critical roles for c-Myb in lymphoid priming and early B-cell development. , 2010, Blood.

[35]  A. Look,et al.  Mechanisms of transcription factor deregulation in lymphoid cell transformation , 2007, Oncogene.

[36]  Rochelle A. Diamond,et al.  Notch/Delta signaling constrains reengineering of pro-T cells by PU.1 , 2006, Proceedings of the National Academy of Sciences.

[37]  Y. Okuno,et al.  Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter is required for myeloma cell growth. , 2007, Cancer research.

[38]  B. Calabretta,et al.  Granulocytic differentiation of normal hematopoietic precursor cells induced by transcription factor PU.1 correlates with negative regulation of the c-myb promoter. , 1997, Blood.

[39]  Achim Leutz,et al.  Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1 , 2006, Nature Genetics.

[40]  J. Zavadil,et al.  PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation , 2009, Molecular Cancer Research.

[41]  D C Case,et al.  Clinical staging of chronic lymphocytic leukemia. , 1977, The Journal of the Maine Medical Association.

[42]  A. Rossi,et al.  Epstein–Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-κB pathway , 2008, Nucleic acids research.

[43]  K. Rai,et al.  Diagnosing and treating chronic lymphocytic leukemia in 2009. , 2009, Oncology.

[44]  Wayne Tam,et al.  Accumulation of miR-155 and BIC RNA in human B cell lymphomas. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Mark J. Thomas,et al.  A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis , 1981, Cancer.

[46]  Domenico Coppola,et al.  MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA , 2008, Molecular and Cellular Biology.

[47]  Anton J. Enright,et al.  microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. , 2007, Immunity.

[48]  P. Neiman,et al.  Myc Oncogene-Induced Genomic Instability: DNA Palindromes in Bursal Lymphomagenesis , 2008, PLoS genetics.

[49]  M. Sigvardsson,et al.  The roles of transcription factors in B lymphocyte commitment, development, and transformation , 2004, Journal of leukocyte biology.

[50]  N. Rajewsky,et al.  Regulation of the Germinal Center Response by MicroRNA-155 , 2007, Science.

[51]  ONSTANZE,et al.  GENOMIC ABERRATIONS AND SURVIVAL IN CHRONIC LYMPHOCYTIC LEUKEMIA , 2010 .

[52]  N. Rajewsky,et al.  MiR-150 Controls B Cell Differentiation by Targeting the Transcription Factor c-Myb , 2007, Cell.

[53]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Kutok,et al.  Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1 , 2004, Nature Genetics.