Action of Interferon in Chronic Myelogenous Leukemia

描述：(申请人提供)：干扰素α(IFNA)具有显著的 慢性粒细胞白血病(CML)治疗中的临床活性 其抗白血病作用的机制尚不清楚。我们 已经发现了一种由I型干扰素受体激活的新的信号级联， 涉及到小的GTP酶rac1和p38的MAPK。这条途径起作用 独立于状态通路，但与之合作，以调节 IFNA敏感基因的转录调控。我们的数据表明 这一信号级联在CML患者的原始粒细胞中被激活 而这种对其激活的药物阻断可以逆转这种生长 干扰素对原发白血病骨髓祖细胞的抑制作用。这 建议是一种系统的方法来确定信号机制，通过它 IFNA显示出其抗白血病作用。具体目标A是确定 I型干扰素调节p38通路激活的机制 Bcr-abl表达细胞中的受体及其下游效应分子的鉴定 机械装置。将进行研究以确定Jak激酶和Jak激酶的作用 VaV原癌基因产物对Rac1/p38通路激活的影响 Bcr-abl在细胞中的表达及确定p38依赖核的作用 组蛋白丝氨酸磷酸化在慢性粒细胞白血病细胞诱导IFNA反应中的作用。 具体目标B是确定激活的生物后果 P38在慢性粒细胞白血病。它将涉及研究，以确定rac1和p38是否 对产生IFNA的生长抑制作用是必不可少的 原发白血病祖细胞以及该通路的激活是否存在缺陷 与IFNA耐药相关。它还将检验IFNA的假设 通过p38依赖机制下调bcr-abl蛋白表达。 具体目标C包括研究，以确定 Bcr-abl-酪氨酸激酶拮抗IFNA依赖的基因转录和 确定BCR-ABL特异性抑制剂STI571是否促进生长 IFNA通过对rac1/p38和Jak/Stat的调节作用抑制细胞周期 小路。总而言之，这些研究应该提供关于 慢性粒细胞白血病1型干扰素受体信号转导机制的研究 细胞，促进我们对IFNA发生机制的认识 抵抗。确定这类机制将有助于发展 克服干扰素耐药的新治疗方法和新的设计 治疗慢性粒细胞白血病的药理药物。

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.