alitretinoin and Leukemia-Lymphoma--Adult-T-Cell

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

Topics: Adjuvants, Immunologic; Alitretinoin; Antineoplastic Agents; B-Lymphocytes; Bexarotene; Diphtheria Toxin; Gene Expression Regulation; Humans; Interleukin-2; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Interleukin-2; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Retinoids; T-Lymphocytes; Tetrahydronaphthalenes; Transcription Factors; Tretinoin; Tumor Cells, Cultured

The translocation t(11;16)(q23;p13) has only been documented in patients with acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We have established a myeloid cell line (SN-1) with the MLL-CBP fusion gene from an acute leukemia patient with t(11;16)(q23;p13). Although SN-1 cells were not induced to differentiate by all-trans retinoic acid (ATRA) and 1alpha,25-dihydroxyvitamin D(3) (VD3), retinoid X receptor (RXR) agonists, such as 9-cis retinoic acid and Ro48-2250, effectively induced differentiation of the cells. Downregulation of the expression of the MLL-CBP fusion gene occurred during the differentiation of SN-1 cells. When SN-1 cells were treated with MLL-CBP antisense oligonucleotide, the cells were induced to differentiate by ATRA or VD3, suggesting that the MLL-CBP fusion gene dominant-negatively suppresses ATRA- or VD3-induced differentiation. Moreover, suboptimal concentrations of sodium butyrate, a histone deacetylase inhibitor, had a cooperative effect with ATRA or VD3 in inducing the differentiation of SN-1 cells. The downregulation of the expression of MLL-CBP mRNA was accompanied by the induction of differentiation. These findings suggest that RXR agonists or a clinically applicable combination of ATRA and butyrate derivatives might be useful for differentiation therapy in leukemia patients with the MLL-CBP fusion gene.

Topics: Alitretinoin; Antineoplastic Agents; Artificial Gene Fusion; Butyric Acid; Calcitriol; Cell Differentiation; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 16; CREB-Binding Protein; DNA-Binding Proteins; Gene Expression Regulation, Leukemic; Histone-Lysine N-Methyltransferase; Humans; Leukemia-Lymphoma, Adult T-Cell; Myeloid-Lymphoid Leukemia Protein; Nuclear Proteins; Oligonucleotides, Antisense; Proto-Oncogenes; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Trans-Activators; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured