Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies.
The homeobox gene PROX1 is related to the Drosophila prospero gene, which is expressed in the developing central nervous system and lens-secreting cone cells. We found that the PROX1 gene had missense and nonsense mutations in 4 of 29 hematologic cell lines analyzed. Decreased mRNA expression was also observed in half of these cell lines by RT-PCR. The restoration of PROX1 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as bisulfite sequencing analysis, indicated that gene silencing is caused by DNA hypermethylation at intron 1. Such hypermethylation was also seen in primary lymphomas (56.3%, 18/32) in a tumor-specific manner. These findings indicate that the profile of the PROX1 gene corresponds to that of a candidate tumor-suppressor gene.
Nagai
Hirokazu
H
1st Department of Internal Medicine, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan. nagaih@nnh.hosp.go.jp
Li
Yinghua
Y
Hatano
Sonoko
S
Toshihito
Ohno
O
Yuge
Masayuki
M
Ito
Etsuro
E
Utsumi
Makoto
M
Saito
Hidehiko
H
Kinoshita
Tomohiro
T
D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D019169:Jurkat Cells; D020014:K562 Cells; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D013447:Sulfites / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D020298:U937 Cells; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D013447:Sulfites; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D001374:Azacitidine; C042345:hydrogen sulfite