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 Harhaj, Izidore S. Lossos, William J. Harrington

Research output: Contribution to journalArticle

49 Citations (Scopus)

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

Fingerprint

Adult T Cell Leukemia Lymphoma
T-cells
Antiviral Agents
Tumors
Neoplasms
Taxation
Interferon-alpha
rel Genes
Chemotherapy
Zidovudine
Oncogene Proteins
Therapeutics
Human T-lymphotropic virus 1
Gene Rearrangement
Genes
Survivors
interferon regulatory factor-4
Clone Cells
T-Lymphocytes
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ramos, J. C., Ruiz, P., Ratner, L., Reis, I. M., Brites, C., Pedroso, C., ... 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
Ramos, Juan Carlos ; Ruiz, Phillip ; Ratner, Lee ; Reis, Isildinha M. ; Brites, Carlos ; Pedroso, Celia ; Byrne, Gerald E. ; Toomey, Ngoc L. ; Andela, Valentine ; Harhaj, Edward ; Lossos, Izidore S. ; Harrington, William J. / IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. In: Blood. 2007 ; Vol. 109, No. 7. pp. 3060-3068.
@article{ecc95ec18f434da0850a4cb06ed9686d,
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-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.",
author = "Ramos, {Juan Carlos} and Phillip Ruiz and Lee Ratner and Reis, {Isildinha M.} and Carlos Brites and Celia Pedroso and Byrne, {Gerald E.} and Toomey, {Ngoc L.} and Valentine Andela and Edward Harhaj and Lossos, {Izidore S.} and Harrington, {William J.}",
year = "2007",
month = "4",
day = "1",
doi = "10.1182/blood-2006-07-036368",
language = "English (US)",
volume = "109",
pages = "3060--3068",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "7",

}

Ramos, JC, Ruiz, P, Ratner, L, Reis, IM, Brites, C, Pedroso, C, Byrne, GE, Toomey, NL, Andela, V, Harhaj, E, Lossos, IS & Harrington, WJ 2007, 'IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma', Blood, vol. 109, no. 7, pp. 3060-3068. https://doi.org/10.1182/blood-2006-07-036368

IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. / Ramos, Juan Carlos; Ruiz, Phillip; Ratner, Lee; Reis, Isildinha M.; Brites, Carlos; Pedroso, Celia; Byrne, Gerald E.; Toomey, Ngoc L.; Andela, Valentine; Harhaj, Edward; Lossos, Izidore S.; Harrington, William J.

In: Blood, Vol. 109, No. 7, 01.04.2007, p. 3060-3068.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma

AU - Ramos, Juan Carlos

AU - Ruiz, Phillip

AU - Ratner, Lee

AU - Reis, Isildinha M.

AU - Brites, Carlos

AU - Pedroso, Celia

AU - Byrne, Gerald E.

AU - Toomey, Ngoc L.

AU - Andela, Valentine

AU - Harhaj, Edward

AU - Lossos, Izidore S.

AU - Harrington, William J.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33947596860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947596860&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-07-036368

DO - 10.1182/blood-2006-07-036368

M3 - Article

C2 - 17138822

AN - SCOPUS:33947596860

VL - 109

SP - 3060

EP - 3068

JO - Blood

JF - Blood

SN - 0006-4971

IS - 7

ER -

Ramos JC, Ruiz P, Ratner L, Reis IM, Brites C, Pedroso C et al. IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood. 2007 Apr 1;109(7):3060-3068. https://doi.org/10.1182/blood-2006-07-036368