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

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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.