title: MicroRNA biogenesis is required for Myc-induced B-cell lymphoma development and survival.
abstract: Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre(+)/Emicro-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre(+)/Dicer(fl/fl)/Emicro-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival.
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Arrate
authors.forename: Tiffaney
authors.initials: T
authors.lastname: Vincent
authors.forename: Jessica
authors.initials: J
authors.lastname: Odvody
authors.forename: Rekha
authors.initials: R
authors.lastname: Kar
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D004722:Endoribonucleases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D016259:Genes, myc; D016158:Genes, p53; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D043244:Ribonuclease III
chemical_list: D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases