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

基本信息

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
项目类别：
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&apos 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

项目摘要

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) 是美国第七大常见癌症，也是最主要的癌症血液系统恶性肿瘤的类型——占所有诊断病例的约 50%，尽管情况较好。了解其遗传库、控制独特转录和信号传导的因素不同 B-NHL 亚类的依赖性仍不完全清楚，因此，临床反应。标准护理疗法具有高度异质性，因此迫切需要确定新的治疗方法。量身定制的治疗策略可提供更有效和持久的反应。在这里，我们展示了谱系决定转录因子 PRDM 家族的成员 (PRDM15) 在 B 细胞恶性肿瘤中异常上调，建议评估其作为新型药物的潜力我们的初步数据强烈支持 PRDM15 可以被耗尽而不会产生重大副作用。然而，在体内，靶向清除癌前 B 细胞将大大延迟淋巴瘤的发生。从机制上讲，PRDM15 通过转录调节肿瘤促进代谢途径（例如， PI3K/AKT，糖酵解），虽然对于稳态条件下的 B 细胞分化来说是可有可无的， PRDM15 在 B 细胞激活过程中发挥作用，显着导致代谢变化，相当于发生于淋巴瘤。我们研究 PRDM15 调节蛋白质的转录，从而调节蛋白质的表达（例如 IGF1R、INSR、HK3）参与生理 B 细胞免疫引起的基本代谢变化该项目旨在更好地将 PRDM15 定义为癌症的关键调节因子。我们建议在以下过程中研究这一中心假设。具体目标：在目标 1 中，我们将评估 PRDM15 在肿瘤发生和维持中的机制作用以及具体而言，为了评估 PRDM15 在特定肿瘤亚群中的治疗潜力，我们将重点关注。在目标 2 中，我们将研究 B 细胞淋巴瘤中最终由 PRDM15 调节的下游基因和通路。描述 PRDM15 在稳态和稳态时在正常造血和 B 细胞反应中的作用外部挑战（例如接触外来抗原、骨髓重建）这两者都相关。了解 PRDM15 在正常 B 细胞分化中的作用并评估其潜力针对 PRDM15 功能的疗法的风险或副作用。这些研究的意义在于，考虑到 PRDM15 对于代谢重连的重要性激活和转化的 B 细胞，了解 PRDM15 的作用机制，将能够靶向其降解或抑制其功能，可能具有未来的治疗相关性。与健康相关的是，我们的研究可能会为各种 B- 具有高能量需求的细胞淋巴瘤。