p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells
S. Takemoto et al., p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells, BLOOD, 95(12), 2000, pp. 3939-3944
Human T-cell lymphotropic virus type I (HTLV-I) transforms T cells in vitro
, and the viral transactivator Tax functionally impairs the tumor suppresso
r p53 protein, which is also stabilized in HTLV-I-infected T cells. Thus, t
he functional impairment of p53 is essential to maintain the viral-induced
proliferation of CD4+ mature T cells. However, in the CD4+ leukemic cells o
f patients with adult T-cell leukemia/lymphoma (ATLL), the viral transactiv
ator does not appear to be expressed, and p53 mutations have been found onl
y in a fraction of patients. We sought to investigate whether p53 function
is impaired, in ex vivo samples from patients with ATLL, in the absence of
genetic mutations. Here we demonstrate that the p53 protein is stabilized a
lso in ex vivo ATLL samples (10 of 10 studied) and that at least in 2 patie
nts p53 stabilization was not associated with genetic mutation. Furthermore
, the assessment of p53 function after ionizing radiation of ATLL cells ind
icated an abnormal induction of the p53-responsive genes GADD45 and p21(WAF
1) in 7 of 7 patients. In 2 of 2 patients, p53 regulation of cell-cycle pro
gression appeared to be impaired as well. Because p53 is part of a regulato
ry loop that also involves MDM2 and p14(ARF), the status of the latter prot
eins was also assessed in cultured or fresh ATLL cells. The p97 MDM2 protei
n was not detected by Western blot analysis in established HTLV-I-infected
T-cell lines or ex vivo ATLL cell lysates, However, the MDM2 protein could
be easily detected after treatment of cells with the specific proteasome in
hibitor lactacystin, suggesting a normal regulation of the p53-MDM2 regulat
ing loop. Similarly, p14(ARF) did not appear to be aberrantly expressed in
ex vivo ATLL cells nor in any of the established HTLV-l-infected T-cell lin
es studied. Thus, p53 stabilization in HTLV-I infection occurs in the absen
ce of genetic mutation and alteration of the physiologic degradation pathwa
y of p53, (C) 2000 by The American Society of Hematology.