Molecular Mechanisms of Leukemogenesis by PMLRAR alpha

PMLRAR α 导致白血病发生的分子机制

• 批准号: 7759507
• 负责人: SCOTT C. KOGAN
• 金额: $ 28.81万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759507
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Address; Aftercare; Alleles; American; Behavior; Binding Sites; Biology; Cell Separation; Cells; Characteristics; Chromosomal translocation; Chromosomes, Human, Pair 8; Complement; Coupled; Cytokine Receptors; Cytokine Signaling; DAXX gene; Development; Diagnosis; Dimerization; Disease; Drug Delivery Systems; Ensure; Environment; Event; FLT3 gene; Gene Dosage; Gene Expression; Gene Fusion; Gene Targeting; Genes; Genetic; Goals; Growth; Hematopoietic stem cells; Homo; Human; Human Chromosomes; Immune; In Vitro; Investigation; Knowledge; Leukemic Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Nuclear Protein; Nuclear Proteins; Oncogene Proteins; Pathogenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Progranulocytes; Proliferating; RARA gene; Repression; Retroviridae; Role; S100A8 gene; Series; Site; Staging; Stem cells; System; Transgenic Mice; Transplant-Related Disorder; Transplantation; Tretinoin; Trisomy 8; Variant; Work; cellular transduction; chromosome 15 trisomy; chromosome 8 gain; effective therapy; factor C; fusion gene; gene repression; human stem cells; in vivo; inhibitor/antagonist; innovation; insight; kinase inhibitor; leukemia; leukemogenesis; monocyte; mouse model; neutrophil; novel; overexpression; pressure; prevent; progenitor; promoter; public health relevance; response; self-renewal; small hairpin RNA; transcription factor; vector

DESCRIPTION (provided by applicant): Our broad long-term objectives are to delineate the cellular and molecular mechanisms by which genetic changes cooperate to transform myeloid progenitors into acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL), one sub-type of AML, is associated with a chromosomal translocation that fuses the retinoic acid receptor alpha gene (RARA) with the gene encoding the PML nuclear protein. We expressed PML-RAR1 in myeloid cells of mice to generate a mouse model of APL. This model in combination with studies of human APL cells can be used to address central questions in leukemia biology including (i) what cells can accumulate genetic changes such that they become leukemia? (ii) how do initiating events alter cellular behavior? (iii) how do cooperating events further propel cells towards transformation? (iv) once a malignancy has formed, from what cells can the leukemia re-grow after treatment? The specific aims of this proposal are: (1) Identify mechanisms by which PML-RAR1 contributes to leukemia and response to therapy, (2) Characterize the myeloid cells that serve as leukemic stem cells (LSC) in APL and identify mechanisms by which the proliferative potential of these cells is expanded, (3) Illuminate how a common genetic change in human APL, gain of chromosome 8, cooperates with PML- RAR1 in leukemic transformation. For Aim 1, we will assess how various PML-RAR1 related alleles influence proliferative potential and cooperate in leukemic transformation. We will also generate mice carrying an inducible allele of activated FLT3: we will characterize the effects of activating this allele in the presence of PML-RAR1 or variants, and will use this system in combination with studies of human APL cells to identify key transcriptional targets of PML-RAR1. For Aim 2, we will characterize the cells that can transplant disease in our mouse APL model, identify LSC for human APL, and delineate myeloid cells that can be converted to leukemia. We will also assess the impact of environment and therapy on LSC. Further, we will identify genes whose alteration can cooperate with PML-RAR1 to enhance self-renewal of myeloid progenitors. For Aim 3, we will delineate mechanisms through which MYC and TRIB1 (encoded on human chromosome 8) can contribute to APL and assess the potential for targeting MYC therapeutically in AML. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia will be diagnosed in approximately 12,000 Americans this year and, despite improvements in treatment, more than 9,000 will die as a result of their disease. The proposal seeks to understand how genetic changes combine to cause leukemia. The results of the proposed studies should help us to understand acute myeloid leukemia and thereby should aid the development of new treatments for leukemias and other cancers.

描述（由申请人提供）：我们广泛的长期目标是描述细胞和分子机制，通过这些机制，遗传变化合作以将髓样祖细胞转化为急性髓样白血病（AML）。 AML的一种亚型急性寄生虫细胞性白血病（APL）与染色体易位融合了视黄酸受体α基因（RARA）与编码PML核蛋白的基因有关。我们在小鼠的髓样细胞中表达PML-RAR1，以生成APL的小鼠模型。该模型与对人APL细胞的研究结合使用，可用于解决白血病生物学中的中心问题，包括（i）哪些细胞可以积累遗传变化，使其成为白血病？ （ii）启动事件如何改变细胞行为？ （iii）如何使事件合作进一步推动细胞转化？ （iv）一旦形成了恶性肿瘤，治疗后白血病可以从哪些细胞中重新成长？ The specific aims of this proposal are: (1) Identify mechanisms by which PML-RAR1 contributes to leukemia and response to therapy, (2) Characterize the myeloid cells that serve as leukemic stem cells (LSC) in APL and identify mechanisms by which the proliferative potential of these cells is expanded, (3) Illuminate how a common genetic change in human APL, gain of chromosome 8, cooperates with PML- RAR1 in白血病转化。对于AIM 1，我们将评估各种PML-RAR1相关等位基因如何影响增殖潜力并在白血病转化中进行合作。我们还将生成带有活化FLT3的诱导等位基因的小鼠：我们将表征在存在PML-RAR1或变体的情况下激活该等位基因的影响，并将使用该系统与人类APL细胞的研究结合使用该系统来识别PML-RAR1的关键转录靶标。对于AIM 2，我们将表征可以在小鼠APL模型中移植疾病，识别人APL的LSC的细胞，并描绘可以转化为白血病的髓样细胞。我们还将评估环境和治疗对LSC的影响。此外，我们将确定其改变可以与PML-RAR1合作的基因，以增强髓样祖细胞的自我更新。对于AIM 3，我们将描述MYC和TRIB1（在人类8号染色体上编码）的机制，可以为APL做出贡献，并评估在AML中靶向MYC的潜力。公共卫生相关性：今年大约有12,000名美国人将诊断出急性髓细胞性白血病，尽管治疗有所改善，但由于他们的疾病，将会死亡9,000多个。该提案试图了解遗传变化如何结合起来引起白血病。拟议的研究的结果应有助于我们了解急性髓样白血病，从而有助于开发白血病和其他癌症的新疗法。