HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia.
In the pathogenesis of adult T cell leukemia (ATL), an oncogenetic role of the human T cell lymphotropic virus type I (HTLV-I) Tax protein, viral escape from the host immune system, and host genetic changes have been proposed as contributory factors. We examined the premature stop codons in tax gene as one of the mutations that may lead to escape of HTLV-I from the cytotoxic T lymphocyte (CTL) response in HTLV-I carriers, to test whether a putative CTL escape mutant can emerge in the early stage of ATL development and whether HTLV-I infected cells with such a mutation can proliferate subsequently. We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations. The premature stop codon in tax gene existed in many non-ATL HTLV-I carriers as a minor population but not in the commonest HTLV-I sequence of the individual. This minor population with a premature stop codon did not expand subsequently in 3 asymptomatic carriers tested. There were cases who had a mutation or deletion in HTLV-I who also have either deletion of INK4 genes or mutation in p53 gene. Our findings suggest that CTL escape mutation can occur at an early stage of ATL development, and that certain host genetic changes favor the development of the aggressive form of ATL.
Furukawa
Yoshitaka
Y
Division of Blood Transfusion Medicine and Cell Therapy, Kagoshima University Hospital, Kagoshima, Japan. furukawy@m2.kufm.kagoshima-u.ac.jp
Tara
Mitsutoshi
M
Izumo
Shuji
S
Arimura
Kimiyoshi
K
Osame
Mitsuhiro
M
D049109:Cell Proliferation; D002470:Cell Survival; D018389:Codon, Nonsense; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000502:physiology; D016158:Genes, p53; D016355:Genes, pX / Q000235:genetics*; D015490:HTLV-I Infections / Q000150:complications; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology*; D011379:Prognosis
D018389:Codon, Nonsense; D050756:Cyclin-Dependent Kinase Inhibitor Proteins