Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue.
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.
Karenko
Leena
L
Department of Dermatology and Venereology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. leena.p.karenko@hus.fi
Hahtola
Sonja
S
Päivinen
Suvi
S
Karhu
Ritva
R
Syrjä
Sanna
S
Kähkönen
Marketta
M
Nedoszytko
Boguslaw
B
Kytölä
Soili
S
Zhou
Ying
Y
Blazevic
Vesna
V
Pesonen
Maria
M
Nevala
Hanna
H
Nupponen
Nina
N
Sihto
Harri
H
Krebs
Inge
I
Poustka
Annemarie
A
Roszkiewicz
Jadwiga
J
Saksela
Kalle
K
Peterson
Pärt
P
Visakorpi
Tapio
T
Ranki
Annamari
A
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
D007376:Interleukin-2; D008565:Membrane Proteins; C464453:NAV3 protein, human; D009419:Nerve Tissue Proteins