Human Hematopoietic Cell Transformation by BCR/ABL

BCR/ABL 人类造血细胞转化

• 批准号: 7455926
• 负责人: RAVI BHATIA
• 金额: $ 36.05万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455926
• 关键词: Actins; Adhesions; Apoptosis; BCR/ABL fusion gene; Binding; Biochemical; C-terminal; CD34 gene; Cell Line; Cell model; Cells; Chemotaxis; Chronic; Chronic Myeloid Leukemia; Clinical; Complex; Defect; Development; Ectopic Expression; Fibronectins; Genes; Goals; Growth; Growth Factor; Hematological Disease; Hematopoietic; Human; Imatinib; Imatinib mesylate; Malignant - descriptor; Mediating; Modeling; Molecular; Mus; Mutation; Myeloid Leukemia; Myeloproliferation; Oncogenes; PTPN11 gene; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Proline-Rich Domain; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Regulation; Resistance; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Stem cells; Tertiary Protein Structure; Tyrosine; Tyrosine Kinase Inhibitor; abl Oncogene; adapter protein; base; bcr-abl Fusion Proteins; cell transformation; cell type; improved; kinase inhibitor; leukemogenesis; migration; novel; progenitor; response; small molecule; trafficking

DESCRIPTION (provided by applicant): Chronic myelogenous leukemia (CML) results from the transformation of a very primitive hematopoietic cell by the BCR/ABL oncogene and is characterized by increased myeloproliferation and abnormal trafficking of malignant progenitors. CML progenitors demonstrate several abnormalities in hematopoietic regulation including increased growth factor-induced proliferation, reduced adhesion to fibronectin and reduced chemotaxis towards SDF-1a. Although the tyrosine kinase inhibitor imatinib mesylate is very effective in the treatment of CML, elimination of malignant progenitors is often incomplete and clinical resistance can occur. Therefore, additional treatment approaches to target BCR/ABL activated signaling mechanisms important for transformation are of high priority. The contribution of different BCR/ABL mechanisms to transformation varies from 1 cell type to the other, and the contribution of known mechanisms to human hematopoietic cell transformation is not clear. The goal of the proposed studies is to investigate molecular mechanisms that are critical for human progenitor transformation. In preliminary studies, we have investigated abnormalities in intracellular signaling in CD34+ progenitor cells from CML patients. We have also developed a novel CML model based on ectopic expression of the BCR/ABL gene in human CD34+ cells, which reproduces abnormalities in hematopoietic regulation seen in primary CML progenitors and facilitates study of molecular mechanisms of transformation. Preliminary studies have identified BCR/ABL protein domains that may significantly contribute to abnormal progenitor growth and adhesion. In Specific Aim 1 we will investigate the role of an autophosphorylation site at BCR Y177 and downstream signaling through Grb2, Gab2 and Shp2 in abnormal proliferation and apoptosis of BCR/ABL expressing human progenitors. In Specific Aim 2 we will investigate the mechanisms of abnormal adhesion and chemotaxis in BCR/ABL transformed human progenitors. Finally, in Specific Aim 3 we will investigate whether inhibition of the above signaling pathways can enhance suppression of CML progenitors growth when combined with imatinib, and/or can suppress growth of progenitors resistant to imatinib because of kinase domain mutations. These studies are expected to result in improved understanding of mechanisms critical for human progenitor transformation in CML and guide rational development of additional mechanism-based therapies.

描述（由申请人提供）：慢性髓性白血病（CML）是由BCR/ABL癌基因转化非常原始的造血细胞引起的，其特征是骨髓增殖增加和恶性祖细胞的异常运输。CML祖细胞在造血调节中表现出几种异常，包括生长因子诱导的增殖增加、与纤连蛋白的粘附减少和对SDF-1 a的趋化性降低。虽然酪氨酸激酶抑制剂甲磺酸伊马替尼在治疗CML中非常有效，但恶性祖细胞的消除通常是不完全的，并且可能发生临床耐药性。因此，靶向对转化重要的BCR/ABL活化信号传导机制的额外治疗方法具有高度优先性。不同的BCR/ABL机制对转化的贡献从一种细胞类型到另一种细胞类型是不同的，已知机制对人类造血细胞转化的贡献尚不清楚。拟议研究的目标是研究对人类祖细胞转化至关重要的分子机制。在初步研究中，我们已经调查了CML患者的CD 34+祖细胞的细胞内信号传导异常。我们还开发了一种新的CML模型的基础上异位表达的BCR/ABL基因在人CD 34+细胞，再现造血调控异常的主要CML祖细胞，并促进转化的分子机制的研究。初步研究已经确定了BCR/ABL蛋白结构域，可能显着有助于异常祖细胞生长和粘附。在特定目标1中，我们将研究BCR Y177的自磷酸化位点和通过Grb 2、Gab 2和Shp 2的下游信号传导在表达BCR/ABL的人祖细胞的异常增殖和凋亡中的作用。在特定目标2中，我们将研究BCR/ABL转化的人祖细胞中异常粘附和趋化性的机制。最后，在具体目标3中，我们将研究当与伊马替尼组合时，抑制上述信号通路是否可以增强对CML祖细胞生长的抑制，和/或是否可以抑制由于激酶结构域突变而对伊马替尼耐药的祖细胞的生长。这些研究有望提高对CML中人类祖细胞转化关键机制的理解，并指导其他基于机制的疗法的合理开发。