title: A fluorescence in situ hybridization map of 6q deletions in acute lymphocytic leukemia: identification and analysis of a candidate tumor suppressor gene.
abstract: With the objective of identifying candidate tumor suppressor genes, we used fluorescence in situ hybridization to map leukemia-related deletions of the long arm of chromosome 6 (6q). Twenty of 24 deletions overlapped to define a 4.8-Mb region of minimal deletion between markers D6S1510 and D6S1692 within chromosome 6 band q16. Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC). Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL). Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient. The substitution was absent among 232 normal alleles tested, leaving open the possibility that heterozygous carriers of such mutations may be susceptible to ALL. Although low in all normal hematopoietic tissues, quantitative reverse transcription-PCR showed higher baseline GRIK2 expression in thymus and T cells than other lineages. Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P = 0.0001). By contrast, elevated GRIK2 expression was measured in the myelomonocytic line THP-1 and in one patient with common ALL. Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types.
authors.affiliation: Haematology Department, Royal Free and University College School of Medicine, London, United Kingdom.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Sinclair
authors.forename: Amani
authors.initials: A
authors.lastname: Sorour
authors.forename: Mary
authors.initials: M
authors.lastname: Martineau
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Mitchell
authors.forename: Elena
authors.initials: E
authors.lastname: O'Neill
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D016147:Genes, Tumor Suppressor; D006413:Hematopoietic System / Q000378:metabolism / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097806:GluK2 Kainate Receptor
chemical_list: D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor