SEARCH FOR SELECTIVE THERAPY OF CML

寻找 CML 的选择性治疗

• 批准号: 2406307
• 负责人: BAYARD D CLARKSON
• 金额: $ 87.62万
• 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 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2406307
• 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)祖细胞之间的关系 以开发新的、更具选择性的治疗方法。CML是一种 发展选择性治疗的极佳靶点，因为它的高度 一致的9；22染色体易位，导致BCR融合 和ABL基因以及一种新的与构成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 对慢性病的所有初期表现负全部责任 CML的阶段，因此是人类早期形式的一个极好的模型 癌症。虽然目前尚不清楚p210bcr/abl如何扭曲 其结构性酪氨酸激酶活性的调控途径被认为 改变关键调节蛋白的正常磷酸化模式 在信号转导通路中，因此引导 增殖和成熟的有序顺序不正确 受监管的。最终结果是细胞核和核子的不同步发育 细胞质，细胞比正常情况下经历更多的分裂 他们的成熟。这项研究计划由三个相互关联的 旨在了解BCR/ABL蛋白如何扭曲 信号通路。项目1侧重于确定以下方面的差异 在可比原生代中组成酪氨酸磷酸化的蛋白质 高度浓缩的正常和CML早期祖细胞。在预赛中 研究表明，一种组成酪氨酸的pp62蛋白具有 在纯化的CML原始细胞中始终发现不是 在类似的正常母细胞中可以检测到；这种蛋白质将被提纯并 特色化的。项目1还旨在设计一个新的数学模型 的可能性，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的主要目标是 了解p210bcr/abl的磷酸化与其 功能以及这些磷酸化和功能是如何在 表达p210 bcr/abl的人骨髓细胞与表达c-abl的人髓系细胞的比较 和正常髓系细胞中的bcr蛋白。项目#3还旨在研究 酪氨酸磷酸化在慢性粒细胞白血病中的作用，但将集中在 催化去磷酸化的酶，即PTPase。尤其是， 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 主要使用有无p210的细胞系来表征 相互作用，但丰富的初级正常和CML冲击波也将 比较一下。在过去，慢性粒细胞白血病经常是人类肿瘤的典范， 这项研究的新发现可能会让我们更好地理解 具有特定基因缺陷的其他类型的早期癌症。