Selective Abrogation of STAT5 Expression Impairs the Proliferation of Acute Myeloid Leukemia Cells with Various Cytogenetic Alterations

STAT5 is a key common downstream mediator of multiple signaling pathways which are often dysregulated in various hematologic malignancies, including acute myeloid leukemia (AML). Due to the heterogeneity and high relapse rate of the disease, the treatment options for AML are currently limited. Although the approach of treating the disease by inhibiting upstream kinases such as FLT3 within these signaling pathways appeared promising, the clinical efficacy of these drugs as mono-therapy have been disappointing. We hypothesized that this lack of efficacy might be due to the residual STAT5 activity that is present even in the presence of these inhibitors in vivo. Therefore, abrogating the expression of the final regulator of these pathways, STAT5, might be a much more efficient way of blocking signaling, thus inhibiting the proliferation and survival of AML cells. In this study, we first investigated the role of STAT5 in the proliferation of AML cells by selectively suppressing the expression of the gene using 2^nd-Generation antisense oligonucleotides (ASOs). Suppression of STAT5 following ASO treatment (>80% over control ASO) led to a significant inhibition of cell proliferation (50~70% over control ASO), a decrease in colony formation, and a modest induction of apoptosis in a range of AML lines including KG-1α, MV-4-11, and MOLM-13. STAT5 ASO treatment was highly specific for the STAT5 target and produced predictable effects on gene expression, as demonstrated by the downregulation of Pim-1 and cyclin D1, well-known STAT5 regulated genes. No changes in the expression levels of Bcl-XL, STAT1, and STAT3 were observed. Furthermore, relative anti-proliferative activity within the various AML lines correlated well with the relative levels of STAT5 activity. Interestingly, there was a strong correlation between the extent of STAT5/Pim-1 downregulation and the degree of anti-proliferation, suggesting a possible role of Pim-1 as a downstream effector of STAT5 ASO anti-proliferative activity. Studies comparing the relative effects of the STAT5 ASO inhibitor with the potent multi kinase inhibitor CEP701 in various AML cell lines demonstrated potent anti-proliferative activity for the STAT5 inhibitor in the cell lines including KG-1α that display resistance to the multi kinase inhibitor. Taken together, these results suggest that a STAT5 ASO therapeutic approach may have utility for the treatment of AML and related hematologic disorders.