Action of Interferon in Chronic Myelogenous Leukemia

性状：（由申请人提供）：干扰素α（IFNa）具有显著的 治疗慢性粒细胞白血病（CML）的临床活性，但 其显示抗白血病作用的机制仍不清楚。我们 已经鉴定了由I型IFN受体激活的新型信号级联， 涉及小的GT3激酶Rac 1和p38 Map激酶。这条通路作用于 独立于Stat-pathway，但与之合作，调节 IFN α敏感基因的转录调控。我们的数据证明 这种信号级联在CML患者的原代粒细胞中被激活 而药理学上阻断其激活可以逆转 IFN α对原代白血病骨髓祖细胞的抑制作用这 建议是一个系统的方法来确定信号机制， IFNa具有抗白血病作用。具体目标A是确定 I型IFN对p38通路激活的调节机制 BCR-ABL表达细胞中的受体，并鉴定下游效应子 机制等将进行研究以确定Jak激酶的作用， vav原癌基因产物对Rac1/p38通路激活的影响 表达BCR-ABL的细胞，并确定p38依赖性核表达的作用。 组蛋白丝氨酸磷酸化在CML细胞中诱导IFN α应答中的作用 具体目标B是确定激活的生物学后果， CML中的p38。它将涉及确定Rac 1和p38是否 对于IFNa对细胞的生长抑制作用的产生至关重要， 原发性白血病祖细胞以及该通路是否有缺陷激活 与IFNa抗性相关。它还将检验IFNa的假设 通过p38依赖性机制下调BCR-ABL蛋白表达。 具体目标C包括开展研究，以确定 BCR-ABL-酪氨酸激酶拮抗IFN α依赖性基因转录， 确定BCR-ABL特异性抑制剂STI571是否增加了生长， IFNa通过调节Rac1/p38和Jak/Stat的抑制作用 途径。总之，这些研究应提供关于 CML中1型IFN受体转导信号的机制 细胞和推进我们对IFNa的发展机制的知识 阻力确定这些机制将有助于发展 克服IFN α抗性的新治疗方法和新的抗干扰素治疗剂的设计 用于治疗CML的药物。

DESCRIPTION: (provided by applicant): Interferon alpha (IFNa) has significant clinical activity in the treatment of chronic myelogenous leukemia (CML), but the mechanisms by which it exhibits its antileukemic effects remain unknown. We have identified a novel signaling cascade activated by the Type I IFN receptor, involving the small GTPase Rac1 and the p38 Map kinase. This pathway acts independently of the Stat-pathway, but in cooperation with it, to regulate transcriptional regulation of IFNa-sensitive genes. Our data demonstrate that this signaling cascade is activated in primary granulocytes from CML patients and that pharmacological blockade of its activation reverses the growth inhibitory effects of IFNa on primary leukemia bone marrow progenitors. This proposal is a systematic approach to identify the signaling mechanisms by which IFNa exhibits its antileukemic effects. Specific aim A is to determine the mechanisms of regulation of activation of the p38 pathway by the Type I IFN receptor in BCR-ABL expressing cells and to identify downstream effector mechanisms. Studies will be performed to determine the roles of Jak kinases and the vav proto-oncogene product on the activation of the Rac1/p38 pathway in BCR-ABL expressing cells and to define the role of p38-dependent nuclear histone serine phosphorylation in the induction of IFNa-responses in CML cells. Specific aim B is to determine the biological consequences of activation of p38 in CML. It will involve studies to determine whether Rac1 and p38 are essential for the generation of the growth inhibitory effects of IFNa on primary leukemic progenitors and whether defective activation of this pathway correlates with IFNa-resistance. It will also examine the hypothesis that IFNa downregulates BCR-ABL protein expression via a p38-dependent mechanism. Specific aim C includes studies to identify the mechanisms by which the BCR-ABL-tyrosine kinase antagonizes IFNa-dependent gene transcription and determine whether the BCR-ABL specific inhibitor, STI571, augments the growth inhibitory effects of IFNa via regulatory effects on the Rac1/p38 and Jak/Stat pathways. Altogether, these studies should provide important information on the mechanisms by which signals are transduced by the Type 1 IFN receptor in CML cells and advance our knowledge on the mechanisms of development of IFNa resistance. Identifying such mechanisms will facilitate the development of novel therapeutic approaches to overcome IFNa-resistance and the design of new pharmacologic agents for the treatment of CML.