Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma.
Adult T-cell leukemia/lymphoma (ATLL) is caused by latent human T-lymphotropic virus-1 (HTLV-1) infection. To clarify the molecular mechanism underlying leukemogenesis after viral infection, we precisely mapped 605 chromosomal breakpoints in 61 ATLL cases by spectral karyotyping and identified frequent chromosomal breakpoints in 10p11, 14q11, and 14q32. Single nucleotide polymorphism (SNP) array-comparative genomic hybridization (CGH), genetic, and expression analyses of the genes mapped within a common breakpoint cluster region in 10p11.2 revealed that in ATLL cells, transcription factor 8 (TCF8) was frequently disrupted by several mechanisms, including mainly epigenetic dysregulation. TCF8 mutant mice frequently developed invasive CD4(+) T-cell lymphomas in the thymus or in ascitic fluid in vivo. Down-regulation of TCF8 expression in ATLL cells in vitro was associated with resistance to transforming growth factor beta1 (TGF-beta1), a well-known characteristic of ATLL cells, suggesting that escape from TGF-beta1-mediated growth inhibition is important in the pathogenesis of ATLL. These findings indicate that TCF8 has a tumor suppressor role in ATLL.
Hidaka
Tomonori
T
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan.
Nakahata
Shingo
S
Hatakeyama
Kinta
K
Hamasaki
Makoto
M
Yamashita
Kiyoshi
K
Kohno
Takashi
T
Arai
Yasuhito
Y
Taki
Tomohiko
T
Nishida
Kazuhiro
K
Okayama
Akihiko
A
Asada
Yujiro
Y
Yamaguchi
Ryoji
R
Tsubouchi
Hirohito
H
Yokota
Jun
J
Taniwaki
Masafumi
M
Higashi
Yujiro
Y
Morishita
Kazuhiro
K
D000818:Animals; D019457:Chromosome Breakage; D002879:Chromosomes, Human, Pair 10; D002883:Chromosomes, Human, Pair 14; D015536:Down-Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007621:Karyotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1