title: Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice.
abstract: Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Here we identified Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation, as a mutational target in spontaneous and radiation-induced T-cell lymphomas in Mlh1-deficient mice. Three quarters of lymphomas lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Mononucleotide repeat sequences at 1029-1034(C)6 and 1567-1572(G)6 in Ikaros were mutational hot spots with a one-base deletion occurring with a frequency of 45 and 50%, respectively. Point mutations and splicing alterations were also observed. In total, 85% of the lymphomas showed aberrations in Ikaros. The characteristic of Mlh1-deficient lymphomas is harboring of multiple mutations simultaneously in the same tumor, displaying a combination of two frameshift mutations at different repeats, frameshift and point mutations, and/or deletion mutations. This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis.
authors.affiliation: Experimental Radiobiology for Children's Health Research Group, National Institute of Radiological Sciences, Chiba, Japan. skakinum@nirs.go.jp
authors.forename: S
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Y
authors.initials: Y
authors.lastname: Kodama
authors.forename: Y
authors.initials: Y
authors.lastname: Amasaki
authors.forename: S
authors.initials: S
authors.lastname: Yi
authors.forename: Y
authors.initials: Y
authors.lastname: Tokairin
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: M
authors.initials: M
authors.lastname: Monobe
authors.forename: S
authors.initials: S
authors.lastname: Kojima
authors.forename: Y
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D018450:Disease Progression; D016368:Frameshift Mutation; D051740:Ikaros Transcription Factor / Q000502:physiology*; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D000070957:MutL Protein Homolog 1