The principle objective of this proposal is to characterize the clinical and biologic relevance of a novel ATP-binding cassette (ABC) cytokine transporter, ABC-1, in acute myeloid leukemia (AML). Resistance to chemotherapy remains the major obstacle limiting the success of conventional treatment for patients with AML. Delineation of biological features which contribute to chemotherapy resistance, therefore, is of paramount importance to the development of more effective treatment strategies. The ABC-1 gene encodes a novel cyclosporine (CSP)-inhibitable transmembrane transporter responsible for interleukin-1 beta (IL-1beta) secretion. Preliminary investigations show that ABC-1 and IL-1 beta are coordinately overexpressed in 65 percent of cases of high-risk AML, and that CSPs inhibit IL-1 beta secretion and enhance antineoplastic cytotoxicity in IL-1 beta autocrine-responsive AML progenitors, independent of P-glycoprotein (PGP) expression. Because autocrine and paracrine stimulation by IL-1 beta has been implicated in the promotion of leukemia progenitor self-renewal, the applicants hypothesize that expression of ABC-1 and IL-1 beta is associated with autonomous in vitro formation of AML progenitors, and that inhibition of ABC-1 transport function by CSPs contributes to improved treatment outcome in PGP patients in clinical trials testing the benefit of CSP modulation of chemotherapy resistance. Expression of ABC-1 and IL-1 beta gene RNA will be assessed by RT-PCR in pretreatment and relapsed AML specimens from SWOG trials 9126 and 9918, and in normal hematopoietic elements enriched by cell sorting. ABC-1 specific antibodies will be generated for immunodetection of the ABC-1 protein, and correlated with gene message and autonomous leukemia progenitor formation. These investigations will address the following specific aims: (1) to assess the prognostic relevance of ABC-1 overexpression in poor-risk AML; (2) assess the relation between ABC-1 and CSP-inhibitable autonomous in vitro growth of AML progenitors and other biologic features; (3) delineate the pattern of ABC-1 gene expression in normal hematopoietic elements; and (4) investigate in a preliminary fashion whether the addition of CSPs to conventional chemotherapy promotes more effective elimination of ABC-1+ blast populations.
