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: 10533775
• 负责人: Ernesto Guccione
• 金额: $ 48.03万
• 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/10533775
• 关键词: Acceleration; 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; Cellular biology; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Binding; Data; Dependence; Development; Diagnosis; Disease Progression; Embryonic Development; Exposure to; FRAP1 gene; Family; Family member; 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; Process; Proteins; Receptor Activation; Resistance; Risk; Role; Signal Transduction; Structure of germinal center of lymph node; TCF3 gene; Therapeutic; Therapeutic Intervention; Tumor Promotion; Up-Regulation; Work; Zinc Fingers; 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.

概括 B细胞非霍奇金淋巴瘤（B-NHL）是美国第七大癌症，主要是主要癌症 血液学恶性肿瘤的类型 - 占所有诊断病例的约50％。尽管更好 了解其遗传库，管理独特转录和信号的因素 不同B-NHL子类的依赖性尚不完全理解。因此，对 护理标准疗法是高度异质的。因此，迫切需要识别小说 量身定制的治疗策略，可提供更有效和耐用的反应。 在这里，我们证明了PRDM谱系的成员决定转录因子 （PRDM15）在B细胞恶性肿瘤中绝对上调，并提出评估其作为新颖的潜力的建议 药物目标。我们的初步数据强烈支持PRDM15可以耗尽而不会产生重大不利影响 体内。然而，在恶性前B细胞细胞中的靶向耗竭将强烈延迟淋巴作用。 从机械上讲，PRDM15通过转录调节促进肿瘤的代谢途径起作用（例如， PI3K/AKT，糖酵解）。有趣的是，虽然在稳态条件下可用于B细胞分化，但 PRDM15在B细胞激活期间起作用，这尤其导致代谢变化等同于那些 发生在淋巴瘤中。 我们假设PRDM15调节转录，因此是蛋白质的表达 （例如IGF1R，INSR，HK3）参与物理B细胞免疫实施的必需代谢变化 激活或致癌转化。该项目旨在更好地将PRDM15定义为 在这些过程中代谢重新布线。我们建议在下面研究这一中心假设 具体目的：在AIM1中，我们将评估PRDM15在肿瘤倡议和维护中的机理作用以及 评估靶向特定肿瘤子集中PRDM15的治疗潜力。具体来说，我们将集中精力 在B细胞淋巴瘤中PRDM15调控的下游基因和途径上。在目标2中，我们将 在稳定状态和在 外部挑战（例如暴露于外国抗原，骨髓重建）。这两个都将是相关的 了解PRDM15在正常B细胞​​分化的背景下的作用并评估潜力 针对PRDM15功能的疗法的风险或副作用。 这些研究的意义在于，鉴于PRDM15对于代谢重新布线的重要性 激活和转化的B细胞了解PRDM15的作用机理，将允许其定位 降解或抑制其功能，并且可能具有未来的治疗意义。 健康相关性是，我们的研究可能会为各种B-确定新的治疗机会 具有高能量需求的细胞淋巴瘤。