Since the first reports of adult T-cell leukemia (ATL) in the 1970s,1, 2
decades of studies have focused on this hematological malignancy because of its unique late-onset clinical manifestations, the dysregulation of the interleukin 2 (IL-2) receptor and the causative agent, human T-cell leukemia virus type I (HTLV-I).3, 4, 5
The pathogenesis of ATL is a multistep process because overt leukemia develops in some HTLV-I carriers after a long latent period.6
It is thought that in the initial stage of leukemogenesis, HTLV-I-infected CD4+
T cells grow on the condition that IL-2 is available, whereas in the terminal and acute stage of ATL, these cells expand independently of growth factors in vivo
Many HTLV-I-infected T-cell lines derived from ATL patients need to be maintained initially in the presence of IL-2 (IL-2-dependent growth stage (D stage)), although the same cell lines spontaneously acquire independence of exogenous IL-2 supplementation later during the long-term culture (IL-2-independent growth stage (I stage)). On the basis of the parallelism between in vivo
and in vitro
growth of ATL cells, the in vitro
transition from IL-2-dependent to -independent growth has been a useful model for investigating the mechanism by which ATL develops in vivo
, as well as for exploring possible strategies to treat this leukemia.9, 10, 11
Glucocorticoid (GC) has been included in the standard therapy of hematological malignancies.12, 13
However, GC is of limited use in the treatment of ATL owing to the frequent occurrence of GC resistance and exacerbation of the immunosuppressive status inherently associated with this leukemia.14
The mechanism for the lack of GC efficacy seen in ATL cases remains unclear. GC receptor (GR), represented by the functional α isoform (GRα), mediates most of the pleiotropic GC activities. Upon ligand binding, GR translocates from the cytoplasm to the nucleus and regulates the expression of target genes through trans-activation or trans-repression mechanism.15, 16
Extensive studies have been conducted to clarify the mechanism by which HTLV-I affects GR signaling, revealing that the oncoprotein Tax1 encoded by HTLV-I plays a critical role in repressing nuclear receptor-dependent transcription.17, 18
Tax1 also affects nuclear factor-κB and signal transducer and activator of transcription 5 signaling, both of which are major downstream targets of GR signaling.19, 20
Taken together, there is a unique alteration in the responsiveness to GC in ATL.
Thioredoxin is a 12-kDa protein that harbors the CXXC motif and plays a critical role in redox regulation. After reporting that thioredoxin was expressed in ATL cells at an extremely high level,21
our studies have focused on the role of thioredoxin in the leukemogenesis by HTLV-I. A yeast two-hybrid assay allowed us to identify thioredoxin-binding protein-2 (TBP-2/VDUP-1/TXNIP) as an endogenous binding partner and antagonist of thioredoxin.22
Thioredoxin and TBP-2 are involved in the ASK1-dependent apoptosis pathway.23, 24
Blocking thioredoxin of cancer cells was suggested to be a useful approach to cancer therapy.25, 26
TBP-2 is induced by GC in murine normal thymocytes and the T-cell lymphoma line WEHI7.2.27
Intriguingly, TBP-2 expression is lost during the progression of HTLV-I-induced transformation.28, 29
On the basis of these observations, we hypothesized that TBP-2 plays a critical role in GC-induced ATL cell death. If this is the case, it is possible that the diversity in the GC efficacy in treating ATL patients is explained by the expression of TBP-2.
In this study, we used a series of HTLV-I-infected T-cell lines independently established from ATL patients and found that the GR–TBP-2 signaling axis plays a key role in mediating GC-induced cell death.