The role of AF10 in normal and leukemic hematopoiesis

AF10 在正常和白血病造血中的作用

• 批准号: 8601977
• 负责人: Aniruddha J. Deshpande
• 金额: $ 8.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-11-08 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601977
• 关键词: role; AF10; normal; leukemic; hematopoiesis

DESCRIPTION (provided by applicant): The overall goal of this project is to offer novel insights into the mechanisms of epigenetic deregulation in hematological malignancies that may lead to improved therapeutic strategies. Leukemias bearing chromosomal rearrangements of the AF10 transcription factor are marked by specific perturbations of chromatin 1-3, thereby providing an excellent model for the study of epigenetic deregulation in oncogenesis. We hypothesize that epigenetic dysregulation in the AF10 leukemias results from the loss of the N-terminal PHD domains of AF10 and the retention of the C-terminal octapeptide motif-leucine zipper (OM-LZ) domain in oncogenic AF10 fusions. Our preliminary observations show that transformation by AF10 fusion oncogenes can be suppressed by inhibiting the activity of the AF10 OM-LZ domain or alternatively, by restoring the PHD zinc finger domain in oncogenic AF10 fusions. These observations hold great therapeutic promise for the AF10 leukemias. In Specific Aim 1, we propose to identify mechanisms that lead to tumor suppression using established models of leukemia and knockout mice, followed by high throughput approaches. The clinical relevance of these studies is borne out by the fact that AF10 is involved in recurrent chromosomal translocations in a wide variety of hematological malignancies 4-8. Moreover, several other cancers share features common to the AF10 leukemias, notably - involvement of PHD domains 9-12 or the histone methyltransferase DOT1L 13 together with deregulation of the developmentally critical HOX genes 14, 15. The proposed studies may therefore yield valuable insights into common mechanisms of HOX gene deregulation in cancer. Our preliminary results support a role for AF10 in the regulation of mammalian HOX genes. Deregulation of this function seems to be a critical event in oncogenesis of AF10 leukemias. Therefore, to gain insights into the role of AF10 in normal and leukemic hematopoiesis, we propose to identify the role of AF10 in normal and leukemic hematopoiesis using biochemical and gene-targeting approaches. Specifically, we plan to characterize the transcriptional activity of AF10 and establish conditional knockout mice with hematopoietic specific deletions of AF10 in Specific Aim 2. Prior studies support a role for AF10 in the regulation of HOX genes 1, 2, 16, 17. Establishment of AF10 knockout mice will enable assessment of AF10 function including potential regulation of HOX genes that have important roles in normal and malignant hematopoiesis. Since the AF10-DOT1L network is a valuable therapeutic target, identification of components of this network may provide critical information for its potential pharmacologic inhibition. The proposed project will be carried out in a rich academic institutional environment, and will be guided a mentoring committee composed of renowned scientists. The proposal is supported by a strong training component that includes didactic and practical instruction in epigenetics and hematopathology, training in the responsible conduct of research, and acquisition of mentoring abilities for successfully transitioning to an independent investigator.

描述（由申请人提供）：该项目的总体目标是为血液恶性肿瘤中表观遗传失调的机制提供新的见解，从而可能改进治疗策略。携带 AF10 转录因子染色体重排的白血病以染色质 1-3 的特定扰动为标志，从而为研究肿瘤发生中的表观遗传失调提供了一个极好的模型。我们假设 AF10 白血病的表观遗传失调是由于 AF10 N 端 PHD 结构域的丢失和致癌 AF10 融合中 C 端八肽基序亮氨酸拉链 (OM-LZ) 结构域的保留所致。我们的初步观察表明，可以通过抑制 AF10 OM-LZ 结构域的活性或通过恢复致癌 AF10 融合中的 PHD 锌指结构域来抑制 AF10 融合癌基因的转化。这些观察结果为 AF10 白血病带来了巨大的治疗前景。在具体目标 1 中，我们建议使用已建立的白血病模型和基因敲除小鼠来确定导致肿瘤抑制的机制，然后采用高通量方法。 AF10 参与多种血液恶性肿瘤中的复发性染色体易位这一事实证实了这些研究的临床相关性 4-8。此外，其他几种癌症具有 AF10 白血病的共同特征，特别是 - 涉及 PHD 结构域 9-12 或组蛋白甲基转移酶 DOT1L 13 以及发育关键 HOX 基因 14、15 的失调。因此，拟议的研究可能会产生有价值的见解HOX 基因失调在癌症中的常见机制。我们的初步结果支持 AF10 在哺乳动物 HOX 基因的调节中发挥作用。该功能的失调似乎是 AF10 白血病肿瘤发生的关键事件。因此，为了深入了解 AF10 在正常和白血病造血中的作用，我们建议使用生化和基因靶向方法来确定 AF10 在正常和白血病造血中的作用。具体来说，我们计划表征 AF10 的转录活性，并在特定目标 2 中建立具有造血特异性删除 AF10 的条件敲除小鼠。先前的研究支持 AF10 在 HOX 基因 1、2、16、17 的调节中的作用。 AF10 基因敲除小鼠将能够评估 AF10 功能，包括 HOX 基因的潜在调节，这些基因在正常和恶性造血中发挥重要作用。由于 AF10-DOT1L 网络是一个有价值的治疗靶点，因此鉴定该网络的组成部分可能为其潜在的药理抑制提供关键信息。拟议的项目将在丰富的学术机构环境中进行，并将由著名科学家组成的指导委员会指导。该提案得到了强大的培训内容的支持，其中包括表观遗传学和血液病理学的教学和实践指导、负责任的研究行为培训以及获得成功过渡为独立研究者的指导能力。