SEARCH FOR SELECTIVE THERAPY OF CML

寻找 CML 的选择性治疗

• 批准号: 6495836
• 负责人: BAYARD D CLARKSON
• 金额: $ 13.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-29 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6495836
• 关键词: cellular oncology; chronic myelogenous leukemia; molecular oncology; myeloid stem cell; neoplasm /cancer therapy

The major goal of this program is to define the critical differences between normal and chronic myelogenous leukemia (CML) progenitor cells in order to develop leads for new, more selective therapy. CML is an excellent target for developing selective treatment because of its highly consistent 9;22 chromosome translocation, resulting in fusion of the bcr and abl genes and a novel fusion gene product with constitutive tyrosine kinase activity, p210bcr/abl. The fused bcr/abl gene is thought to be solely responsible for all the initial manifestations of the chronic phase of CML, and thus is an excellent model of an early form of human cancer. While it is not yet known how p210bcr/abl distorts the regulatory pathways its constitutive tyrosine kinase activity is thought to alter the normal pattern of phosphorylation of key regulatory proteins in the signal transduction pathways so that the genes that direct the orderly sequence of proliferation and maturation are not properly regulated. The end result is asynchronous development of the nucleus and cytoplasm, and the cells go through more divisions than normal during their maturation. This Research Program consists of three interrelated projects directed at understanding how the bcr/abl protein distorts the signaling pathways. Project #1 focuses on identifying differences in proteins constitutively phosphorylated on tyrosine in comparable primary highly enriched normal and CML early progenitor cells. In preliminary studies, a pp62 protein constitutively phosphorylated on tyrosine has consistently been found in purified CML blast cells that is not detectable in comparable normal blasts; this protein will be purified and characterized. Project #1 also aims to design a new mathematical model of CML, and to investigate the possibility of developing a specific immunologic (T cell mediated) therapy directed at the unique bcr/abl junction amino acid sequences. The main aim of Project #2 is to understand how the phosphorylation of p210bcr/abl relates to its functions and how these phosphorylations and functions are altered in human myeloid cells expressing p210 bcr/abl compared to those on c-abl and bcr proteins in normal myeloid cells. Project #3 also aims to study the role of tyrosine phosphorylation in CML, but will focus on the enzymes catalyzing dephosphorylation, the PTPases. In particular, the interaction between PTP1B and both c-abl and P210bcr/abl will be studied, defining interaction domains and the enzymatic and biological consequences of the association. Projects #2 and #3 will initially mainly use cell lines with and without p210 to characterize the interactions, but enriched primary normal and CML blasts will also be compared. CML has often been an exemplar of human neoplasia in the past, and new findings from this research may lead to better understanding of other types of early cancers with specific genetic defects.

该计划的主要目标是定义关键差异 正常和慢性粒细胞白血病 (CML) 祖细胞之间 以便开发新的、更具选择性的治疗方法。 CML 是一种 开发选择性治疗的绝佳目标，因为其高度 一致的 9;22 染色体易位，导致 bcr 融合 和abl基因以及一种新型的具有组成型酪氨酸的融合基因产物 激酶活性，p210bcr/abl。 融合的 bcr/abl 基因被认为是 慢性病所有最初表现的唯一责任 CML 阶段，因此是人类早期形式的优秀模型 癌症。 虽然目前尚不清楚 p210bcr/abl 如何扭曲 其组成型酪氨酸激酶活性被认为是调节途径 改变关键调节蛋白磷酸化的正常模式 在信号转导途径中，指导基因 增殖和成熟的有序顺序不正确 受监管。 最终结果是 core 的异步开发 细胞质中，细胞比正常情况下经历更多的分裂 他们的成熟。 该研究计划由三个相互关联的项目组成 旨在了解 bcr/abl 蛋白如何扭曲 信号通路。 项目#1 侧重于识别差异 在可比较的原代中，蛋白质在酪氨酸上组成型磷酸化 高度富集的正常和 CML 早期祖细胞。 在初步 研究发现，酪氨酸组成型磷酸化的 pp62 蛋白 在纯化的 CML 母细胞中一致发现， 在可比较的正常爆炸中可检测到；该蛋白质将被纯化并且 特点。 项目#1还旨在设计一个新的数学模型 CML 的研究，并研究开发特定的 CML 的可能性 针对独特的 bcr/abl 的免疫学（T 细胞介导）疗法 连接氨基酸序列。 项目#2 的主要目标是 了解 p210bcr/abl 的磷酸化如何与其相关 功能以及这些磷酸化和功能如何在 与表达 c-abl 的人骨髓细胞相比，表达 p210 bcr/abl 的人骨髓细胞 和正常骨髓细胞中的 bcr 蛋白。 项目#3也旨在研究 酪氨酸磷酸化在 CML 中的作用，但将重点关注 催化去磷酸化的酶，PTPases。 特别是， 将研究 PTP1B 与 c-abl 和 P210bcr/abl 之间的相互作用， 定义相互作用域以及酶和生物 协会的后果。 项目 #2 和 #3 最初将 主要使用含有和不含p210的细胞系来表征 相互作用，但富集的原代正常细胞和 CML 母细胞也将 比较的。 过去，CML 常常是人类肿瘤的一个典型， 这项研究的新发现可能会让我们更好地理解 具有特定遗传缺陷的其他类型的早期癌症。