Karenko Leena, Hahtola Sonja, Päivinen Suvi, Karhu Ritva, Syrjä Sanna, Kähkönen Marketta, Nedoszytko Boguslaw, Kytölä Soili, Zhou Ying, Blazevic Vesna, Pesonen Maria, Nevala Hanna, Nupponen Nina, Sihto Harri, Krebs Inge, Poustka Annemarie, Roszkiewicz Jadwiga, Saksela Kalle, Peterson Pärt, Visakorpi Tapio, Ranki Annamari
Department of Dermatology and Venereology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Cancer Res. 2005 Sep 15;65(18):8101-10. doi: 10.1158/0008-5472.CAN-04-0366.
Multicolor fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sézary 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 Sézary 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 Sézary 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.
多色荧光原位杂交（FISH）用于鉴定12例蕈样肉芽肿或 Sézary 综合征患者获得性染色体畸变，这两种疾病是原发性皮肤T细胞淋巴瘤（CTCL）最常见的形式。最常受累的染色体是12号染色体，在连续7例 Sézary 综合征患者中的5例中，该染色体显示克隆性缺失或易位，断点位于12q21或12q22，第6例患者显示克隆性单体。平衡易位t(12;18)(q21;q21.2)的断点定位在两个缺失的最小共同区域，精细定位到12q2。通过位点特异性FISH，该易位破坏了一个基因NAV3（POMFIL1），它是秀丽隐杆线虫unc-53的人类同源物。在6例有缺失或易位的病例中，有1例在剩余的NAV3等位基因中发现了一个错义突变。通过位点特异性FISH，在8例早期蕈样肉芽肿（IA-IIA期）患者中的4例（50%）皮肤病变以及13例晚期蕈样肉芽肿或 Sézary 综合征患者中的11例（85%）皮肤或淋巴结中发现了NAV3缺失。在Jurkat细胞和原代淋巴细胞中基于慢病毒小干扰RNA的NAV3沉默的初步功能研究显示白细胞介素2表达增强（但CD25表达未增强）。因此，NAV3可能在CTCL细胞的生长、分化和凋亡以及疾病进展过程中从Th1型向Th2型表型的转变中发挥作用。NAV3是一种新型的假定单倍体不足肿瘤抑制基因，在最常见类型的CTCL大多数病例中被破坏，因此可能提供一种新的诊断工具。
