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Acute Myeloid Leukemia (AML) affects nearly 500,000 individuals annually, making it a prominent avenue of study. About 30% of patients express a genetic insertion mutation within the FLT3 receptor (known as FLT3-ITD) responsible for regulating the hematopoietic process of these cells, worsening patient prognosis. Whether this is caused by the overactive FLT3 or specifically the JAK2/STAT5 pathway activated by FLT3 is unknown, making both FLT3 and JAK2 inhibition important options to consider. Current treatments of FLT3-mutated AML include FLT3 inhibitors but are not specific to FLT3 and act as broad-spectrum tyrosine kinase inhibitors. A newly developed, highly specific FLT3-ITD inhibitor (known as FLT3-IN-3) may provide new treatment options. Another drug, known as BMS 911543, is a potent JAK2 inhibitor and may lead to similar or improved results compared to a specific FLT3 inhibitor by allowing other pathways within the FLT3 signaling cascade to continue without the increase in cellular proliferation from the JAK2/STAT5 pathway. With further investigation into the FLT3/JAK2/STAT5 pathway, and based on previous research, Vitamin A may be a novel treatment option in combination with one of these inhibitors as it also acts through a JAK2 signaling cascade. Vitamin A is currently used as a therapeutic agent for the treatment of Acute Promyelocytic Leukemia and has been shown to cause cellular differentiation, but its effects have not been explored in AML. The objective of this study is to utilize three human AML cell lines (MV4-11, PL-21, and NB-4) that range in FLT3-ITD expression to investigate the half-maximal inhibitory concentrations (IC50) of FLT3-IN-3 and BMS 911543, and the effects of these inhibitors and physiological concentrations of Vitamin A to elicit cellular differentiation and apoptosis. Methods include measuring cell death and viability using a hemocytometer and analysis of surface expression of various markers of cellular processes by flow cytometry. Current results have revealed Vitamin A to be potentially cytotoxic to the MV4-11 cell line by inducing apoptosis and a potential differentiation agent in the PL-21 cell line. Ranges of IC50 for both inhibitors have been experimentally determined to be between 12 and 14 nM for FLT3-IN-3 and between 4 and 5 uM for BMS 911543. Utilizing these concentrations, experiments to determine their effects on differentiation and apoptosis will be further investigated. Following completion, these results will allow AML cells to be treated with combinations of Vitamin A and each inhibitor to explore the effectiveness of combination therapy to best treat FLT3-mutated AML cancer patients.
Swanson et al. (Fri,) studied this question.