SELECTIVE THERAPY OF CHRONIC MYELOID LEUKEMIA

慢性粒细胞白血病的选择性治疗

• 批准号: 2107173
• 负责人: BAYARD D CLARKSON
• 金额: $ 53.48万
• 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 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2107173
• 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确定关键的差异 正常和慢性粒细胞白血病（CML）祖细胞之间的关系 以便开发新的、更具选择性的治疗方法。 CML是一种 由于其高度的选择性治疗， 一致的9;22染色体易位，导致bcr融合 和abl基因以及具有组成型酪氨酸的新融合基因产物 融合的bcr/abl基因被认为是p210 bcr/abl激酶活性的一个重要标志。 完全负责所有的慢性病的最初表现， 阶段的CML，因此是一个很好的模型的早期形式的人类 癌 虽然目前还不清楚p210 bcr/abl是如何扭曲 调节途径，其组成型酪氨酸激酶活性被认为 改变关键调节蛋白磷酸化的正常模式 在信号传导途径中， 增殖和成熟的有序顺序并不正确， 监管. 最终的结果是核心的异步开发， 细胞质中，细胞通过更多的分裂比正常期间 他们的成熟。 该研究计划包括三个相互关联的 旨在了解bcr/abl蛋白如何扭曲 信号通路 项目#1侧重于确定 蛋白质组成型磷酸化酪氨酸在相当的初级 高度富集的正常和CML早期祖细胞。 初步 研究表明，一种在酪氨酸上组成性磷酸化的pp 62蛋白， 在纯化的CML原始细胞中始终发现， 在可比较的正常胚细胞中可检测到;该蛋白质将被纯化， 表征了 项目#1还旨在设计一个新的数学模型 的CML，并研究开发一种特定的 针对独特bcr/abl的免疫（T细胞介导）治疗 连接氨基酸序列。 项目#2的主要目的是 了解p210 bcr/abl的磷酸化与其 功能以及这些磷酸化和功能如何在 表达p210 bcr/abl的人髓系细胞与c-abl的人髓系细胞相比 和正常骨髓细胞中的BCR蛋白。 #30003;的目的是研究 酪氨酸磷酸化在CML中的作用，但将重点放在 催化去磷酸化的酶，PTPases。 特别是 将研究PTP 1B与c-abl和P210 bcr/abl之间相互作用， 定义相互作用域， 协会的后果。 项目#2和#3最初将 主要使用具有和不具有p210的细胞系来表征 相互作用，但富集的原代正常和CML原始细胞也将被 比较了 慢性粒细胞白血病在过去常常是人类肿瘤的范例， 这项研究的新发现可能会让我们更好地理解 其他类型的具有特定遗传缺陷的早期癌症。