Project Summary
This project seeks to delineate the way in which PRPS2 (phosphoribosyl pyrophosphate synthetase) LOF
results in selective, metabolic vulnerabilities in lymphoma with c-Myc overexpression. The isoforms of
phosphoribosyl pyrophosphate synthetase (PRPS1 and PRPS2) are the rate limiting step in de novo
nucleotide bio-synthesis as they are the enzymes responsible for the creation of 5-phosphoribosyl-1-
pyrophosphate (PRPP) - a necessary component of all nucleotides including ATP, GTP, and IMP. In order to
meet c-myc over-expressing cells’ demands for anabolic cellular components, they must have access to
increased nucleoside pools. This provides a window of opportunity to use the increased levels of nucleotide
bio-synthesis in B-cells with c-myc over-expression as a means of cancer therapy and therefore the focus of
this investigation is the phosphoribosyl pyrophosphate synthetase enzyme. Recent studies have found
inhibition of nucleotide bio-synthesis via loss of function (LOF) of PRPS2 induces apoptosis in a significant
portion of Burkitt’s lymphoma cells. Elucidating the metabolic vulnerabilities demonstrated by PRPS2 LOF will
inform the community as to what particular biological need is served by PRPS2 as well as underpin new
strategies for combinatorial therapies that target nucleotide biosynthesis. Given the preliminary data generated
by our lab, it is known that cell death upon PRPS2 LOF is cell intrinsic and selective- loss of PRPS1 does not
result in activation of the apoptotic response. This result has remained consistent in in vitro and in vivo models
and provides the basis for further study into ways to exploit this induced synthetic lethality. The most critical
objectives of this proposal are to 1) Determine the mechanism by which some Myc overexpressing lymphoma
cells evade PRPS2 LOF induced apoptosis and 2) Explore if and how dampened nucleotide biosynthesis
sensitizes MYC over expressing malignancies to therapeutics that target nucleotide biosynthesis or nucleoside
economy. We hypothesize that PRPS2 LOF produces a synthetic lethality that can be combined with
pharmacogenomics approaches targeting de novo/ salvage nucleotide bio-synthetic pathways to induce
selective and complete cell death and will analyze this objective through the use of standard dose response
curves, cellular viability assays and metabolic fluxomics to determine uptake, rate, and utilization of adenosine
through key metabolic pathways, and cellular viability assays to determine the degree of rescue achieved by
supplementation. Second, we will determine to what extent does PRPS2 LOF, and therefore dampened
nucleotide biosynthesis, combine with existing therapies to ablate lymphomagenesis in the Eµ- Myc mouse
model.