title: B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells.
abstract: B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1037, Centre de Recherches en Cancérologie de Toulouse, 31300 Toulouse, France.
authors.forename: M P
authors.initials: MP
authors.lastname: Puissegur
authors.forename: R
authors.initials: R
authors.lastname: Eichner
authors.forename: C
authors.initials: C
authors.lastname: Quelen
authors.forename: E
authors.initials: E
authors.lastname: Coyaud
authors.forename: B
authors.initials: B
authors.lastname: Mari
authors.forename: K
authors.initials: K
authors.lastname: Lebrigand
authors.forename: C
authors.initials: C
authors.lastname: Broccardo
authors.forename: F
authors.initials: F
authors.lastname: Nguyen-Khac
authors.forename: M
authors.initials: M
authors.lastname: Bousquet
authors.forename: P
authors.initials: P
authors.lastname: Brousset
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C490798:ARID3A protein, human; D004268:DNA-Binding Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53