RELEVANCE OF THE IL 1B TRANSLOCATOR ABC 1 IN AML

本提案的主要目标是描述 新型ATP结合盒（ABC）细胞因子的临床和生物学相关性 转运蛋白ABC-1在急性髓细胞白血病（AML）中的作用。化疗耐药 仍然是限制常规治疗成功的主要障碍， AML患者。描述有助于 因此，化疗耐药性对于 制定更有效的治疗策略。ABC-1基因编码一种 一种新型的环孢菌素（CSP）-可重复的跨膜转运蛋白， 白细胞介素-1 β（IL-1 β）分泌。初步调查显示， ABC-1和IL-1 β在65%的乳腺癌病例中协同过表达。 高风险AML，且CSP抑制IL-1 β分泌并增强 IL-1 β自分泌反应性AML祖细胞中的细胞毒性， 不依赖于P-糖蛋白（PGP）表达。因为自分泌和旁分泌 IL-1 β的刺激与白血病的促进有关 为了促进祖细胞自我更新，申请人假设ABC-1的表达 IL-1 β与AML的自主体外形成相关 CSPs对ABC-1转运功能的抑制 有助于改善临床试验中PGP患者的治疗结局 测试CSP调节化疗耐药性的益处。表达 ABC-1和IL-1 β基因RNA将在治疗前和治疗后通过RT-PCR进行评估。 来自SWOG试验9126和9918的复发性AML标本，以及正常 通过细胞分选富集的造血成分。ABC-1特异性抗体将 产生的ABC-1蛋白的免疫检测，并与基因 信息和自主白血病祖细胞形成。这些调查将 解决以下具体目标：（1）评估的预后相关性 ABC-1在低危AML中的过度表达;（2）评估ABC-1与AML的关系。 以及AML祖细胞和其他细胞的CSP可诱导的自主体外生长 ABC-1基因在正常乳腺组织中的表达 造血成分;（4）初步调查是否 在常规化疗中加入CSP可以促进更有效的 消除ABC-1+胚细胞群。

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.