Molecular Mechanisms of Leukemogenesis by PMLRAR alpha

PMLRAR α 导致白血病发生的分子机制

• 批准号: 7027760
• 负责人: SCOTT C. KOGAN
• 金额: $ 28.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027760
• 关键词: acute myelogenous leukemia; bone marrow; carcinogenesis; cell differentiation; cell proliferation; chimeric proteins; disease /disorder model; gene expression; genetic transduction; genetically modified animals; interleukin 3; laboratory mouse; model design /development; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; pathologic process; posttranslational modifications; protein protein interaction; protein structure function; receptor; retinoid binding proteins; transcription factor

Acute promyelocytic leukemia (APL) is a form of acute myeloid leukemia (AML) associated with fusion of the retinoic acid receptor alpha gene with the gene encoding the PML nuclear protein. In APL, the leukemic cells are blocked at the promyelocyte stage of differentiation but can be induced to develop into mature neutrophils by treatment with retinoic acid. The use of retinoic acid to treat APL is a successful example of molecularly-targeted cancer therapy. The broad long-term objectives of the proposed work are to identify the combinations of genetic changes that result in AML and to delineate the mechanisms by which these changes transform normal blood cells into leukemias. The ultimate goal is to utilize this knowledge to improve treatment for human patients with leukemias and other malignancies. The specific research proposed in this application utilizes murine models of leukemia to (i) identify activities of the fusion protein PMLRARalpha that contribute to leukemogenesis and (ii) identify the molecular events that cooperate with PMLRARalpha in leukemogenesis. Activities of PMLRARalpha that may contribute to leukemia are abrogation of the normal function of PML and disruption of normal transcription in myeloid cells (including transcriptional repression of retinoic acid responsive target genes as well as inhibition of other transcription factors). The contribution of activities of PMLRARalpha to leukemogenesis will be assessed by expressing altered forms of PMLRARalpha in mice mutant versions of PMLRARalpha differentially impaired for specific functions will be tested for their ability to initiate leukemia. The development of novel retroviral-based models of APL to complement work with transgenic mice should facilitate assessment of the leukemogenic potential of these altered forms of PMLRARalpha. Additional changes that cooperate with PMLRARalpha are required for leukemogenesis in transgenic mice. Although the nature of these cooperating events is not clear, activation of growth factor receptors may contribute to leukemia. This hypothesis will be assessed by transducing PMLRARalpha-expressing bone marrow cells with retroviral vectors that drive expression of activated forms of IL-3 receptor or activated FLT3. Further, various mutant forms of activated receptors will be compared in regard to their ability to cooperate with PMLRARalpha. Correlating the ability of these mutants to cause leukemia with their different effects on growth factor signaling pathways should identify downstream events that have a central role in transformation. In addition, by examining whether the expression or activity of candidate mediators is abnormal in leukemic cells, molecules that participate in the pre-leukemia to leukemia transition will be delineated. The proposed studies should identify molecular pathways and particular molecules that are central to the pathogenesis of AML. This work will aid the development of new molecularly-targeted treatments for these malignancies.

急性临床前白血病（APL）是一种与视黄酸受体α基因融合与编码PML核蛋白的基因相关的急性髓样白血病（AML）。 在APL中，白血病细胞在分化的临时细胞阶段被阻断，但可以通过维甲酸治疗将其诱导成成熟的嗜中性粒细胞。视黄酸用于治疗APL是分子靶向癌症治疗的成功例子。 提出的工作的广泛长期目标是确定导致AML的遗传变化的组合，并描绘这些变化将正常血细胞转化为白血病的机制。 最终目标是利用这些知识来改善白血病和其他恶性肿瘤患者的治疗。 该应用中提出的具体研究利用白血病的鼠模型来（i）识别融合蛋白PMLARALALALPHA的活性，这些活动有助于白血病，并且（ii）确定与PMLRARALALPHA在白血病中配合的分子事件。 可能导致白血病的PMLARALPHA的活性是废除PML的正常功能和髓样细胞中正常转录的破坏（包括视黄酸反应型靶基因的转录抑制以及对其他转录因子的抑制）。 PMLARALALPHA对白血病发生的活性的贡献将通过表达改变的PMLRARALALPHA的变化形式的PMLARALALPHA突变版本的PMLRARALPHA差异损害的特定功能的损害，以供其启动白血病。 基于逆转录病毒的新型APL模型的发展与转基因小鼠相辅相成，应促进评估这些改变形式的PMLRARALALPHA的白血病潜力。 在转基因小鼠中，需要与PMLARALPHA合作的其他变化。 尽管这些合作事件的性质尚不清楚，但生长因子受体的激活可能会导致白血病。 该假设将通过用逆转录病毒载体转导PMLARALALPHA表达PMLARALALPHA的骨髓细胞来评估该假设，这些载体驱动IL-3受体或活化的FLT3的活化形式的表达。 此外，将各种突变形式的激活受体与PMLARALALPHA合作的能力进行比较。 将这些突变体引起白血病的能力与对生长因子信号通路的不同影响相关联，应确定在转化中具有核心作用的下游事件。 此外，通过检查候选介质的表达或活性在白血病细胞中是否异常，将描述参与白血病前与白血病过渡的分子。 拟议的研究应确定分子途径和特定分子，这些分子是AML发病机理的核心。 这项工作将有助于为这些恶性肿瘤开发新的分子治疗方法。