title: Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue.
abstract: 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.
authors.affiliation: Department of Dermatology and Venereology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. leena.p.karenko@hus.fi
authors.forename: Leena
authors.initials: L
authors.lastname: Karenko
authors.forename: Sonja
authors.initials: S
authors.lastname: Hahtola
authors.forename: Suvi
authors.initials: S
authors.lastname: Päivinen
authors.forename: Ritva
authors.initials: R
authors.lastname: Karhu
authors.forename: Sanna
authors.initials: S
authors.lastname: Syrjä
authors.forename: Marketta
authors.initials: M
authors.lastname: Kähkönen
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Nedoszytko
authors.forename: Soili
authors.initials: S
authors.lastname: Kytölä
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Vesna
authors.initials: V
authors.lastname: Blazevic
authors.forename: Maria
authors.initials: M
authors.lastname: Pesonen
authors.forename: Hanna
authors.initials: H
authors.lastname: Nevala
authors.forename: Nina
authors.initials: N
authors.lastname: Nupponen
authors.forename: Harri
authors.initials: H
authors.lastname: Sihto
authors.forename: Inge
authors.initials: I
authors.lastname: Krebs
authors.forename: Annemarie
authors.initials: A
authors.lastname: Poustka
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Roszkiewicz
authors.forename: Kalle
authors.initials: K
authors.lastname: Saksela
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
mesh_terms: D000483:Alleles; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007376:Interleukin-2 / Q000096:biosynthesis; D007399:Interphase / Q000235:genetics; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D012751:Sezary Syndrome / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D007376:Interleukin-2; D008565:Membrane Proteins; C464453:NAV3 protein, human; D009419:Nerve Tissue Proteins