title: Eμ/miR-125b transgenic mice develop lethal B-cell malignancies.
abstract: MicroRNA-125b-1 (miR-125b-1) is a target of a chromosomal translocation t(11;14)(q24;q32) recurrently found in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation results in overexpression of miR-125b controlled by immunoglobulin heavy chain gene (IGH) regulatory elements. In addition, we found that six out of twenty-one BCP-ALL patients without t(11;14)(q24;q32) showed overexpression of miR-125b. Interestingly, four out of nine patients with BCR/ABL-positive BCP-ALL and one patient with B-cell lymphoid crisis that had progressed from chronic myelogenous leukemia overexpressed miR-125b. To examine the role of the deregulated expression of miR-125b in the development of B-cell tumor in vivo, we generated transgenic mice mimicking the t(11;14)(q24;q32) (Eμ/miR-125b-TG mice). Eμ/miR-125b-TG mice overexpressed miR-125b driven by IGH enhancer and promoter and developed IgM-negative or IgM-positive lethal B-cell malignancies with clonal proliferation. B cells obtained from the Eμ/miR-125b-TG mice were resistant to apoptosis induced by serum starvation. We identified Trp53inp1, a pro-apoptotic gene induced by cell stress, as a novel target gene of miR-125b in hematopoietic cells in vitro and in vivo. Our results provide direct evidence that miR-125b has important roles in the tumorigenesis of precursor B cells.
authors: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Y
authors: Y
authors: Enomoto
authors: J
authors: J
authors: Kitaura
authors: K
authors: K
authors: Hatakeyama
authors: J
authors: J
authors: Watanuki
authors: T
authors: T
authors: Akasaka
authors: N
authors: N
authors: Kato
authors: M
authors: M
authors: Shimanuki
authors: K
authors: K
authors: Nishimura
authors: M
authors: M
authors: Takahashi
authors: M
authors: M
authors: Taniwaki
authors: C
authors: C
authors: Haferlach
authors: R
authors: R
authors: Siebert
authors: M J S
authors: MJ
authors: Dyer
authors: N
authors: N
authors: Asou
authors: H
authors: H
authors: Aburatani
authors: H
authors: H
authors: Nakakuma
authors: T
authors: T
authors: Kitamura
authors: T
authors: T
authors: Sonoki
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015139:Blotting, Southern; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D007148:Immunoglobulin mu-Chains; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D012333:RNA, Messenger; D008156:Luciferases