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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2484-2488.
Prepublished online as a Blood First Edition Paper on June 16, 2008; DOI 10.1182/blood-2008-03-141424.
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NEOPLASIA
Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR- receptor
Julie H. Lin1,
Ellen J. Kim1,
Anand Bansal1,
John Seykora1,
Stephen K. Richardson1,
Xian-Yuan Cha1,
Sarosh Zafar1,
Sunita Nasta2,
Maria Wysocka1,
Bernice Benoit1,
Alain H. Rook1, and
Steven S. Fakharzadeh1,3
1 Department of Dermatology, and
2 Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania, Philadelphia; and
3 Philadelphia VA Medical Center, PA
The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)- 2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR- and RXR-β, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR- and RXR-β by resistant cells. We assessed RXR- and RXR-β expression by Western blot analysis and found that resistant cells had significantly decreased RXR- expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR- receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.
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