INTERFERON RESPONSIVENESS IN CML

干扰素蛋白家族目前正在成功应用 到几个临床环境(CML的初始治疗，晚期的治疗 子宫颈癌联合维甲酸治疗和移植后 维持疗法)单独或与其他生物 反应调节剂和化疗药物。在慢性粒细胞白血病中，干扰素 用于新诊断的患者，其中26%的患者足够敏感 干扰素来发展完全的细胞遗传学缓解。干扰素是 目前正在被评估为一种将主要细胞遗传学 自体骨髓移植完成缓解 细胞遗传学缓解，并抑制以下克隆进化 异基因骨髓移植。最具限制性的单一因素 干扰素的用途是从头开始或后天对 干扰素。我们已经成功地分离出了5个监管区域 编码IRF-1和IRF-2转录调控的基因 蛋白质。IRF-1蛋白可能参与决定血管紧张素转换酶 干扰素和干扰素诱导基因的诱导性，以及IRF-2 负向调节干扰素基因。我们和其他人已经确认 其他细胞蛋白质也参与了决定 慢性粒细胞白血病细胞对α-干扰素治疗的敏感性或耐药性。在……里面 此外，我们确定了CML细胞可以通过多种方法 对α-干扰素敏感。我们在这个项目中提议使用 研究其功能特性的动物模型和基因转移方法 在这些分子中，筛选表达或功能的变化 这些分子在慢性粒细胞白血病的进化过程中，并发展了 使用安全修改的病毒来介绍这些的必要信息 分子进入慢性粒细胞白血病细胞，以增加对 α-干扰素。为此，我们开发了一种动物模型 基于紫杉醇化疗和转导的基因选择 病毒诱导的骨髓细胞被用来促进 基因工程造血祖细胞。此外，我们 正在测试这些蛋白质的水平是否与对 以及治疗结果。如果成功，正在开发的方法在 该模型可以应用于允许选择 针对患者的具体治疗形式和向新的发展 慢性粒细胞白血病的治疗形式。

The family of interferon proteins are currently being applied successfully to several clinical settings (initial therapy of CML, therapy of advanced cervical cancer in combination with retinoic acid, and post-transplant maintenance therapy) alone or in combination with other biological response modifiers and chemotherapeutic agents. In CML, interferon is used in newly diagnosed patients, 26% of whom are sufficiently sensitive to interferon to develop complete cytogenetic remissions. Interferon is currently being evaluated as a means to convert major cytogenetic remissions achieved by autologous bone marrow transplants to complete cytogenetic remissions, and to suppress clonal evolution following allogeneic bone marrow transplantation. The single most limiting factor in the utility of interferons is de novo or acquired resistance to interferon. We have succeeded in isolating the 5' regulatory regions of the genes which code for the IRF-1 and IRF-2 transcriptional regulatory proteins. The IRF-1 protein may be involved in determining the level of inducibility of interferon and interferon-inducible genes, and the IRF-2 negatively regulates the interferon genes. We and others have identified additional cellular proteins which are also involved in determining the sensitivity or resistance of CML cells to alpha-interferon therapy. In addition, we identified a number of methods through which CML cells can be sensitized to alpha-interferon. We are proposing in this project to use animal models and gene transfer methods to study the functional properties of these molecules, to screen for changes in the expression or function of these molecules during the evolution of CML, and to develop the information necessary to use safety-modified viruses to introduce these molecules into CML cells for the purposes of increasing the sensitivity to alpha-interferon. For this purpose, we have developed an animal model in which genetic selection, based on Taxol chemotherapy and transduction of virally-induced marrow cells are used to promote the retention of genetically engineering hematopoietic progenitor cells. In addition, we are testing if the levels of these proteins correlate with the response to and outcome of therapy. If successful, the methods under development in this model could be applied to assays which would permit selection of patients for specific forms of therapy and to the development of novel forms of therapy for CML.