title: IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-alpha) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 10; 60%) more often than did sensitive variants (1 of 9; 11%). This finding was independent of the disease form. Elevated expression of the putative c-Rel target, interferon regulatory factor-4 (IRF-4), was observed in 10 (91%) of 11 nonresponders and in all tested patients with c-Rel+ tumors and occurred in the absence of the HTLV-1 oncoprotein Tax. In contrast, tumors in complete responders did not express c-Rel or IRF-4. Gene rearrangement studies demonstrated the persistence of circulating T-cell clones in long-term survivors maintained on antiviral therapy. The expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with antiviral resistance. These molecular features may help guide treatment. AZT and IFN-alpha is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, FL 33136, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ramos
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
authors.forename: Isildinha M
authors.initials: IM
authors.lastname: Reis
authors.forename: Carlos
authors.initials: C
authors.lastname: Brites
authors.forename: Celia
authors.initials: C
authors.lastname: Pedroso
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Byrne
authors.forename: Ngoc L
authors.initials: NL
authors.lastname: Toomey
authors.forename: Valentine
authors.initials: V
authors.lastname: Andela
authors.forename: Edward W
authors.initials: EW
authors.lastname: Harhaj
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: William J
authors.initials: WJ
authors.lastname: Harrington
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D024882:Drug Resistance, Viral; D015870:Gene Expression; D020573:Genes, rel; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D007370:Interferon Type I / Q000627:therapeutic use; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel; D011994:Recombinant Proteins; D015215:Zidovudine / Q000627:therapeutic use; D000099218:Interferon Regulatory Factor-4
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D016328:NF-kappa B; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel; D011994:Recombinant Proteins; D015215:Zidovudine; D000099218:Interferon Regulatory Factor-4; C000715470:MAS1 protein, human; C068059:REL protein, human