Expression of FRA16D/WWOX and FRA3B/FHIT genes in hematopoietic malignancies.
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.
Ishii
Hideshi
H
Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. hishii@ms.jichi.ac.jp
Vecchione
Andrea
A
Furukawa
Yutaka
Y
Sutheesophon
Krittaya
K
Han
Shuang-Yin
SY
Druck
Teresa
T
Kuroki
Tamotsu
T
Trapasso
Francesco
F
Nishimura
Miki
M
Saito
Yasushi
Y
Ozawa
Keiya
K
Croce
Carlo M
CM
Huebner
Kay
K
Furukawa
Yusuke
Y
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
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