title: Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies.
abstract: The WW domain containing oxidoreductase (WWOX) gene was recently identified as a candidate tumor suppressor gene at a common fragile site, FRA16D. Because the fragile histidine triad (FHIT) gene, a tumor suppressor gene encompassing the most active, common fragile site FRA3B, is frequently deleted in various cancers, we evaluated the expression of WWOX and FHIT in 74 cases of primary hematopoietic neoplasias and 20 leukemia cell lines. Aberration or absence of WWOX transcripts was detected in 51% of the primary cases and 55% of cell lines, and three WWOX nucleotide variants were detected among the leukemia cell lines. FHIT expression was absent or altered in 36% of the primary cases and 15% of cell lines. The occurrence of aberrant FHIT reverse transcription-PCR products correlated significantly with the occurrence of WWOX alterations. Wild-type transcripts of both genes were expressed in normal hematopoiesis along with a small fraction of short transcripts. A DNA blot study showed that WWOX and FHIT genes were deleted in 2 of 18 cases with primary acute leukemias; both genes were not expressed in the 2 cases. Furthermore, treatment of cells with a demethylating or histone acetylating agent in culture resulted in increased expression of WWOX and FHIT mRNA in leukemia cells. Conclusions are that WWOX expression is frequently altered or absent in hematopoietic disorders, often in association with FHIT alterations, and that alterations of these fragile genes may result not only from genomic deletions but also from epigenetic modifications associated with expression of fragility.
authors.affiliation: Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. hishii@ms.jichi.ac.jp
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Krittaya
authors.initials: K
authors.lastname: Sutheesophon
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Han
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kuroki
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Miki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saito
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000107:Acetylation; D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D020014:K562 Cells; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins; D020298:U937 Cells; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C486071:WWOX protein, human