IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

Juan Carlos Ramos, Phillip Ruiz, Lee Ratner, Isildinha M. Reis, Carlos Brites, Celia Pedroso, Gerald E. Byrne, Ngoc L. Toomey, Valentine Andela, Edward W. Harhaj, Izidore S. Lossos, William J. Harrington

Research output: Contribution to journalArticle

52 Scopus citations

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-α) 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-α is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely.

Original languageEnglish (US)
Pages (from-to)3060-3068
Number of pages9
JournalBlood
Volume109
Issue number7
DOIs
StatePublished - Apr 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Ramos, J. C., Ruiz, P., Ratner, L., Reis, I. M., Brites, C., Pedroso, C., Byrne, G. E., Toomey, N. L., Andela, V., Harhaj, E. W., Lossos, I. S., & Harrington, W. J. (2007). IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood, 109(7), 3060-3068. https://doi.org/10.1182/blood-2006-07-036368