Physical and Functional Interactions of Acute Myeloid Leukemia-1 with Hypoxia Inducible Factor-1α Protein.

Abstract

Hypoxia inducible factor-1α (HIF-1α), a critical transcription factor for cellular responses to hypoxia, was shown to regulate the differentiation of some kinds of tissue cells including acute myeloid leukemic (AML) cells. Based on the important role of AML1 protein in hematopoietic development, this work tries to investigate the potential relationship of AML1 as well as its abnormal leukemogenic fusion protein AML1-ETO with HIF-1α protein. The results showed that HIF-1α protein physically and directly interacts with ectopically and constitutively expressed AML1 or AML1-ETO protein, as evidenced by integrated Lac operator array, co-immunoprecipitation and GST pull-down assay. It appears that AML1-ETO has better binding ability with HIF-1α protein. With this interaction, either AML1 or AML1-ETO attenuates the transcriptional activity of HIF-1α protein with the inhibition of expressions of vascular endothelial growth factor and glucose transporter-1, two well-known HIF-1α-targeted genes. On the contrary, hypoxia-stabilized HIF-1α protein potentiates transcriptional ability of AML1 and AML1-ETO, as assessed by AML1-binding sites-driven luciferase assay. According to these results, a speculative hypothesis is proposed for the dual roles of HIF-1α in leukemic cell differentiation and angiogenesis. The further investigations would open another avenue of attacking against cancer.