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

总结 B细胞非霍奇金淋巴瘤（B-NHL）是美国第7大最常见的癌症，并且是主要的恶性肿瘤。 恶性血液病类型-占所有诊断病例的~50%。尽管有更好的 了解他们的基因库，控制独特的转录和信号传导的因素， 不同B-NHL亚类的依赖性仍然不完全清楚。因此，临床反应 标准治疗是高度异质的。因此，迫切需要确定新的 定制的治疗策略，提供更有效和持久的反应。 在这里，我们表明，一个成员的PRDM家族的谱系决定转录因子， （PRDM 15）在B细胞恶性肿瘤中异常上调，并建议评估其作为一种新的肿瘤抑制剂的潜力。 药物靶点我们的初步数据强烈支持PRDM 15可以被耗尽而没有重大的不利影响 in vivo.然而，在恶变前B细胞中的靶向消除将强烈延迟淋巴瘤发生。 在机制上，PRDM 15通过转录调节促肿瘤代谢途径（例如， PI 3 K/AKT，糖酵解）。有趣的是，虽然在稳态条件下对B细胞分化进行了研究， PRDM 15在B细胞活化过程中起作用，这显著地导致代谢变化，其相当于那些 发生在淋巴瘤中。 我们假设PRDM 15调节蛋白质的转录，从而调节蛋白质的表达， (e.g. IGF 1 R、INSR、HK 3）参与生理性B细胞免疫引起的基本代谢变化 激活或致癌转化。该项目旨在更好地将PRDM 15定义为 在这些过程中进行代谢重组。我们建议在下面研究这个中心假设 具体目标：在目标1中，我们将评估PRDM 15在肿瘤起始和维持中的机制作用， 以评估靶向PRDM 15在特定肿瘤亚群中的治疗潜力。具体来说，我们将重点 在B细胞淋巴瘤中最终由PRDM 15调节的下游基因和途径。在目标2中， 表征PRDM 15在正常造血和B细胞应答中的作用，无论是在稳态还是在 外部挑战（例如，暴露于外源抗原、骨髓重建）。这将是相关的， 了解PRDM 15在正常B细胞分化中的作用，并评估PRDM 15在正常B细胞分化中的潜在作用。 针对PRDM 15功能的治疗的风险或副作用。 这些研究的重要性在于，考虑到PRDM 15对代谢重新布线的重要性， 激活和转化的B细胞，了解PRDM 15的作用机制，将允许靶向其 降解或抑制其功能，并且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- 细胞淋巴瘤有高能量需求。

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.