RELEVANCE OF THE IL 1B TRANSLOCATOR ABC 1 IN AML

这项提案的主要目标是描述 一种新的三磷酸腺苷结合盒(ABC)细胞因子的临床和生物学相关性 急性髓系白血病(AML)中的转运蛋白ABC-1。对化疗的耐药性 仍然是限制常规治疗取得成功的主要障碍 急性髓系白血病患者。生物特征的描述有助于 因此，对化疗的抗药性是至关重要的 制定更有效的治疗策略。ABC-1基因编码一种 新型环孢素(CSP)可抑制跨膜转运蛋白 白介素1β(IL-1β)分泌。初步调查显示， ABC-1和IL-1β在65%的卵巢癌中协同过度表达 高危AML，CSPs抑制IL-1β分泌并增强 IL-1β自分泌反应性急性髓系白血病祖细胞的抗肿瘤细胞毒性 不依赖于P糖蛋白(Pgp)的表达。因为自分泌和旁分泌 IL-1β的刺激与促进白血病有关 祖细胞自我更新，申请人假设ABC-1的表达 IL-1β与AML体外自主形成相关 祖细胞以及CSP对ABC-1转运功能抑制作用 在临床试验中有助于改善PGP患者的治疗结果 检测CSP对化疗耐药的调节作用。的表达 ABC-1和IL-1β基因的RNA将通过RT-PCR在预处理和 SWOG试验9126和9918复发的AML标本，以及正常 通过细胞分选而丰富的造血元素。ABC-1特异性抗体将 用于ABC-1蛋白的免疫检测，并与基因相关 消息和自主白血病祖细胞的形成。这些调查将 解决以下具体目标：(1)评估患者的预后相关性 ABC-1在低危AML中的过度表达；(2)评估ABC-1与 和CSP抑制的AML祖细胞等体外自主生长 生物学特性；(3)描绘正常组织中ABC-1基因表达模式 造血元素；及(4)初步调查 在常规化疗的基础上增加CSP可促进更有效的治疗 消除ABC-1+BLAST种群。

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.