IRF-4 and Interferon Resistance in Adult T-Cell Leukemia/Lymphoma.

Abstract

Adult T-cell leukemia-lymphoma (ATLL) is a generally fatal CD4 helper T-cell malignancy caused by the human T-cell Leukemia virus type I (HTLV-I). Most ATLL patients fare very poorly with conventional chemotherapy; however interferon-alpha (IFN-α) based antiviral therapy has produced long-term clinical remissions in a subset of patients. Despite this, most patients succumb to their disease regardless of treatment. Little is known about the mechanisms of interferon resistance in ATLL and other tumors. Specific defects in proteins involved or affecting the IFN signaling pathway have been described in other malignancies that are often resistant to interferon, such as cutaneous T-cell lymphoma and melanoma. Many of the elegant molecular pathogenesis studies of ATLL have focused on the viral transactivator Tax, in tax expressing cell lines, although this oncoprotein is not detected in primary unmanipulated tumors. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral (IFN) therapy. Serial ex-vivo analysis of unmanipulated primary leukemic cells obtained from ATLL patients prior to and during induction treatment with parenteral AZT and IFN-α revealed significantly higher induction of IFN regulated genes (Affymetrix gene chip) in patients who had an excellent response to this therapy. Interferon Regulatory Factor 4 (IRF-4) has oncogenic activity in vitro and is expressed in poor prognosis aggressive lymphomas. This transcription factor has also been shown to oppose the antiproliferative effects of interferon perhaps through activity on Toll-like receptor mediated pathways. Analysis of primary unmanipulated ATLL tumors from patients who had received antiviral therapy demonstrated the expression of IRF-4 protein in 7 tumors, 6 of which were from patients who failed this therapy. In contrast, 9 tumors lacked IRF-4 protein, including those from 5 complete and 2 partial responders. Detection of IRF-4 protein by Western blot correlated with high mRNA expression by quantitative RT-PCR studies. Expression of IRF-4 in primary ATLL was independent of the HTLV-I oncoprotein Tax, (which reportedly transactivates this transcription factor). IRF-4 is also a putative target gene of the oncogenic NF-κB subunit c-Rel. We found enhanced nuclear expression of c-Rel in 6 of 7 IRF-4+ ATLL tumors indicating a link between these two anti-apoptotic molecules in ATLL. Finally, PCR based gene rearrangement studies demonstrated the persistence of circulating T-cell clones in our long-term survivors, who have been maintained on AZT and IFN-α for years. In summary, the expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with resistance to IFN-α based therapy. These molecular features may help guide treatment. AZT and IFN-a therapy is a suppressive rather than curative regimen in ATLL, and patients who achieve clinical remission with these drugs should remain on maintenance therapy indefinitely. Studies of the role of IRF-4, c-Rel, and their signaling properties in ATLL are in progress.