DISSECTING THE ROLE OF PRDM15 IN NORMAL HEMATOPOIESIS AND B-CELL MALIGNANCIES

剖析 PRDM15 在正常造血和 B 细胞恶性肿瘤中的作用

• 批准号: 10316262
• 负责人: Ernesto Guccione
• 金额: $ 48.04万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-09 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316262
• 关键词: Accounting; Adult; Adverse effects; Antigens; Antisense Oligonucleotides; B cell differentiation; B lymphoid malignancy; B-Cell Activation; B-Cell Acute Lymphoblastic Leukemia; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BCL2 gene; Binding; Bone Marrow; Burkitt Lymphoma; Cells; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Binding; Data; Dependence; Development; Diagnosis; Disease; Embryonic Development; Exposure to; FRAP1 gene; Family; Family member; Fibrinogen; Future; Genes; Genetic; Genetic Transcription; Glycolysis; Goals; Health; Hematologic Neoplasms; Hematopoiesis; Homeostasis; Human; IGF1R gene; INSR gene; Immune signaling; Incidence; Lesion; Lymphocyte Activation; Lymphoma; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Modeling; Mus; Oncogenic; PAX5 gene; PI3K/AKT; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Process; Proteins; Receptor Activation; Resistance; Risk; Role; Signal Transduction; Structure of germinal center of lymph node; TCF3 gene; Therapeutic; Therapeutic Intervention; Up-Regulation; Work; Zinc Fingers; base; immune activation; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; mTOR inhibition; member; multidisciplinary; new therapeutic target; novel; novel therapeutics; overexpression; premalignant; programs; protein structure; reconstitution; response; side effect; standard of care; targeted treatment; therapeutic target; transcription factor; tumor; tumor growth; tumor initiation

SUMMARY B cell non-Hodgkin Lymphoma (B-NHL) is the 7th most common cancer in the US and the predominant type of hematologic malignancies – accounting for ~50% of all diagnosed cases. Despite a better understanding of their genetic repertoire, the factors governing the unique transcriptional and signaling dependencies of different B-NHL subclasses remain incompletely understood. As such, clinical responses to standard-of-care therapies are highly heterogeneous. There is therefore an urgent need to identify novel tailored therapeutic strategies that provide more effective and durable responses. Here, we show that a member of the PRDM family of lineage determining transcription factors (PRDM15) is abnormally upregulated in B cell malignancies and propose to assess its potential as a novel drug target. Our preliminary data strongly support that PRDM15 can be depleted without major adverse effects in vivo. A targeted depletion in pre-malignant B-cell cells, will however strongly delay lymphomagenesis. Mechanistically, PRDM15 acts by transcriptionally regulating tumor-promoting metabolic pathways (e.g., PI3K/AKT, glycolysis). Interestingly, while dispensable for B cell differentiation under steady state conditions, PRDM15 plays a role during B-cell activation, that notably results in metabolic changes equivalent to those occurring in lymphomas. We hypothesize that PRDM15 modulates transcription, and consequently the expression, of proteins (e.g. IGF1R, INSR, HK3) involved in the essential metabolic changes imposed by physiological B cell immune activation or oncogenic transformation. This project aims to better define PRDM15 as a key regulator of metabolic rewiring during these processes. We propose to investigate this central hypothesis in the following Specific Aims: In Aim1 we will assess the mechanistic role of PRDM15 in tumor initiation and maintenance and to assess the therapeutic potential of targeting PRDM15 in specific tumor subsets. Specifically, we will focus on downstream genes and pathways ultimately regulated by PRDM15 in B cells lymphomas. In Aim 2 we will characterize PRDM15’s role in normal hematopoiesis and B cell responses, both at steady state and upon external challenges (e.g. exposure to foreign antigens, bone marrow reconstitution). This will be relevant both to understand the role of PRDM15 in the context of normal B cell differentiation and to evaluate the potential risks or side effects of therapies targeting PRDM15 functions. The significance of these studies is that given the importance of PRDM15 for metabolic rewiring of activated and transformed B cells, understanding the mechanism of action of PRDM15, will allow targeting its degradation or inhibiting its function and may be of future therapeutic relevance. The health relatedness is that our studies may identify new therapeutic opportunities for a variety of B- cell lymphomas that have high energetic demands.

摘要 B细胞非霍奇金淋巴瘤(B-NHL)是美国第7大最常见的癌症，也是 恶性血液病类型--约占所有确诊病例的50%。尽管有更好的 了解它们的基因谱系，控制独特转录和信号传递的因素 不同B-NHL亚类之间的依赖关系仍不完全清楚。因此，临床反应 标准护理疗法是高度多样化的。因此，迫切需要确定小说 量身定制的治疗策略，提供更有效和持久的反应。 在这里，我们展示了决定转录因子的PRDM家族的一个成员 (PRDM15)在B细胞恶性肿瘤中异常上调，并建议评估其作为新的 毒品目标。我们的初步数据有力地支持了PRDM15可以被耗尽而不会产生重大不利影响 在活体内。然而，对癌前B细胞进行有针对性的清除将大大推迟淋巴肿大的发生。 从机制上讲，PRDM15通过转录调控促进肿瘤的代谢途径发挥作用(例如， PI3K/AKT，糖酵解)。有趣的是，虽然在稳态条件下对B细胞的分化是不必要的， PRDM15在B细胞激活过程中发挥作用，显著地导致相当于 发生在淋巴瘤中。 我们假设PRDM15调节蛋白质的转录，从而调节蛋白质的表达 (如IGF1R、INSR、HK3)参与生理性B细胞免疫所引起的必要代谢变化 激活或致癌转化。该项目旨在更好地将PRDM15定义为 在这些过程中的新陈代谢重新连接。我们建议从以下几个方面研究这一中心假说 具体目标：在Aim1中，我们将评估PRDM15在肿瘤启动和维持以及 目的：评估靶向PRDM15在特定肿瘤亚群中的治疗潜力。具体地说，我们将重点关注 B细胞淋巴瘤中PRDM15最终调控的下游基因和通路。在《目标2》中我们将 PRDM15‘S在稳态和非稳态正常造血和B细胞反应中的作用 外部挑战(例如，暴露于外来抗原、骨髓重建)。这将是两个相关的 了解PRDM15在正常B细胞分化中的作用并评估其潜能 针对PRDM15功能的治疗的风险或副作用。 这些研究的意义在于，鉴于PRDM15对于新陈代谢重排的重要性 激活和转化的B细胞，了解PRDM15的作用机制，将允许靶向其 或抑制其功能，并可能与未来的治疗相关。 与健康相关的是，我们的研究可能会为各种B- 对能量要求很高的细胞性淋巴瘤。