title: Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines.
abstract: Deletion of chromosomal region 13q14 represents the most common genetic aberration in B-cell chronic lymphocytic leukemia (CLL). 13q14 deletions are commonly large and heterogeneous in size and affect multiple genes. We recently found that targeted deletion in mice of the 0.11 megabase (mb)-long minimal deleted region (MDR) encompassing the DLEU2/miR-15a/16-1 cluster recapitulates the spectrum of CLL-associated lymphoproliferations in humans, including CLL, CD5(+) monoclonal B-cell lymphocytosis, and CD5(-) non-Hodgkin lymphomas. In the present study, we demonstrate that additional deletion of the 0.69-mb large genomic region telomeric to the MDR called the common deleted region (CDR) changed the spectrum of lymphoproliferations developing in CDR- versus MDR-deleted mice in that the number of CLL among B-cell lymphoproliferations was significantly elevated in the former. In addition, CDR-deleted mice seemed to succumb to their disease faster than MDR-deleted mice. Comparing HCDR3 regions of CD5(+) lymphoproliferations derived from this and published CLL mouse models, 44% (29 of 66) of junctions could be assigned to 8 sets of highly similar HCDR3 regions, demonstrating that CLL developing in mice frequently expresses almost identical, stereotypic Ag receptors. These results suggest that the size of 13q14 deletions influences the phenotype of the developing lymphoproliferations and potentially the severity of disease, suggesting a tumor-suppressor function for genetic elements in addition to DLEU2/miR-15a/16-1.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Lia
authors.forename: Amanda
authors.initials: A
authors.lastname: Carette
authors.forename: Hongyan
authors.initials: H
authors.lastname: Tang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shen
authors.forename: Tongwei
authors.initials: T
authors.lastname: Mo
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Ulf
authors.initials: U
authors.lastname: Klein
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D018014:Gene Transfer Techniques; D005804:Genes, Lethal / Q000502:physiology; D056426:Genetic Loci / Q000235:genetics / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017384:Sequence Deletion / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D025521:Tumor Suppressor Proteins