The long-term goal of this project is to elucidate the role, regulation and therapeutic potential of sphingomyelin synthase (SMS) in cancer. The current proposal focuses on the function of SMS1 in growth of GATA1 positive leukemic cells (in particular, erythroblasts and megakaryoblasts) and on SMS1 as a potential novel therapeutic target in acute myeloid leukemias (AML) that are enriched in such malignant immature populations (particularly M6 and M7 AML). SMS represents a class of lipid-metabolizing enzymes that consumes ceramide and produces diacylglycerol (DAG), two critical bioactive lipids with opposing functions in the control of key cellular processes often dysregulated during transformation, including proliferation, apoptosis, and differentiation. Thus, SMS may be linked to cancer, but knowledge on SMS regulation and downstream functions is limited. We previously showed that elevated expression of SMS1 is critical for proliferation of erythroleukemic K562 cells. Published and preliminary results also show that the elevated expression of SMS1 is a consequence of enhanced transcription occurring through a novel alternative promoter positively regulated by the transcription factor GATA1. Guided by gene expression data from the Cancer Cell Line Encyclopedia, we discovered that the highest SMS1 expression (mRNA and protein) in blood cancer cells is found in GATA1 positive AML blasts (erythroblasts and megakaryoblasts). Importantly, pharmacological and molecular inhibition of SMS1 in these leukemic cells revealed a critical role for SMS1 in proliferation and survival of these cells that is not observed in GATA1-negative AML blasts. Thus, based on these observations, we hypothesize that SMS1 is an important novel regulator of proliferation and maintenance of GATA1 positive AMLs and a potential novel target for improving the dismal therapeutic response of these leukemias. To address our hypothesis, we will: 1. Determine the role and function of SMS1 in GATA1 positive AML cells and 2. Establish SMS1 as a novel target for therapeutic intervention against GATA1 positive AMLs. Our proposal aims at establishing SMS1 as a novel critical regulator of GATA1+ AML cells and might provide a molecularly informed, and much needed novel therapeutic option for treatment of AML with erythroid or megakaryocytic enrichment.
Acute Myeloid Leukemia (AML) is a blood cancer which presents a mere 26% 5-year overall survival after treatment with chemotherapy and a dismal probability of long term survival. This is mostly due to the presence of residual tumor cells after chemotherapy that have become resistant to the treatment. Unfortunately, the therapeutic regiment for AML has mostly remained the same over the last three decades, thus finding alternative effective treatments for this disease is an urgent unmet need. Since AML is a heterogeneous disease, different therapeutic strategies may be needed to treat specific AML subclasses. Our results have pointed us to investigate the role and function of particular lipids (sphingolipids and glycerolipids) in the regulation of growth and survival of a specific class of AML cells. Moreover the results have also shown promise in sensitization of AML cells to current antileukemic chemotherapy; this would allow us to use lower doses of chemodrugs for the initial treatment of AML leaving the option of escalating the dose in case of insurgence of resistance once the treatment is completed. These are all aspects that we will test with our proposed experimentation.
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