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Primary Cutaneous T-Cell Lymphomas Show a Deletion or Translocation Affecting NAV3, the Human UNC-53 Homologue

Departments of ¹ Dermatology and Venereology and ² Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; ³ Laboratory of Cancer Genetics, ⁴ Institute of Medical Technology, and ⁵ Department of Clinical Genetics, Tampere University Hospital, University of Tampere; ⁶ FIT Biotech, Ltd., Tampere, Finland; ⁷ Department of Dermatology, Medical University of Gdansk, Gdansk, Poland; and ⁸ Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Leena Karenko, Skin and Allergy Hospital, Helsinki University Central Hospital, P.O. Box 160, 00029 HUS, 00250 Helsinki, Finland. Phone: 358-9-471-86267; Fax: 358-9-471-86500; E-mail: leena.p.karenko{at}hus.fi.

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.

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