Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue

被引:69
作者
Karenko, L
Hahtola, S
Päivinen, S
Karhu, R
Syrjä, S
Kähkönen, M
Nedoszytko, B
Kytölä, S
Zhou, Y
Blazevic, V
Pesonen, M
Nevala, H
Kupponen, N
Sihto, H
Krebs, I
Poustka, A
Roszkiewicz, J
Saksela, K
Peterson, P
Visakorpi, T
Ranki, A
机构
[1] Univ Helsinki, Cent Hosp, Dept Dermatol & Venereol, Helsinki, Finland
[2] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland
[3] Tampere Univ, Tampere Univ Hosp, Canc Genet Lab, FIN-33101 Tampere, Finland
[4] Tampere Univ, Tampere Univ Hosp, Inst Med Technol, FIN-33101 Tampere, Finland
[5] Tampere Univ, Tampere Univ Hosp, Dept Clin Genet, FIN-33101 Tampere, Finland
[6] FIT Biotech Ltd, Tampere, Finland
[7] Med Univ Gdansk, Dept Dermatol, Gdansk, Poland
[8] German Canc Res Ctr, Div Mol Genome Anal, D-6900 Heidelberg, Germany
关键词
D O I
10.1158/0008-5472.CAN-04-0366
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Multicolor. fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sezary syndrome, the most common forms of primary cutaneous T-cell lymphoma (CTCL). The most frequently affected chromosome was 12, which showed clonal deletions or translocations with a break point in 12q21 or 12q22 in five of seven consecutive Sezary syndrome patients and a clonal monosomy in the sixth patient. The break point of a balanced translocation t(12;18)(q21;q21.2), mapped in the minimal common region of two deletions, fine mapped to 12q2. By locus-specific FISH, the translocation disrupted one gene, NAV3 (POMFIL1), a human homologue of unc-53 in Caenorhabditis elegans. A missense mutation in the remaining NAV3 allele was found in one of six cases with a deletion or translocation. With locus-specific FISH, NAV3 deletions were found in the skin lesions of four of eight (50%) patients with early mycosis fungoides (stages IA-IIA) and in the skin or lymph node of 11 of 13 (85%) patients with advanced mycosis fungoides or Sezary syndrome. Preliminary functional studies with lentiviral small interfering RNA-based NAV3 silencing in Jurkat cells and in primary lymphocytes showed enhanced interleukin 2 expression (but not CD25 expression). Thus, NAV3 may contribute to the growth, differentiation, and apoptosis of CTCL cells as well as to the skewing from Th1-type to Th2-type phenotype during disease progression. NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool.
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收藏
页码:8101 / 8110
页数:10
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