Submitted March 31, 2008
Accepted May 20, 2008
Clinical and in vitro resistance to bexarotene in adult T cell leukemia: loss of RXR-alpha receptor
Julie H Lin*, Ellen J Kim, Anand Bansal, John Seykora, Stephen K Richardson, Xian-Yuan Cha, Sarosh Zafar, Sunita Nasta, Maria Wysocka, Bernice Benoit, Alain H Rook, and Steven S Fakharzadeh
Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Philadelphia VA Medical Center, Philadelphia, Pennsylvania, United States
* Corresponding author; email: julie.lin{at}mail.mcgill.ca.
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 rapidly responded to combination therapy of bexarotene and interferon (IFN)-
2b with complete clinical response.1 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 RXR receptor subunits, RXR- and RXR-
, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR- and RXR- by resistant cells. We assessed RXR- and RXR-expression by Western blot analysis and found that resistant cells had significantly decreased RXR- expression compared to pre-therapy 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.
