AML1/ETO regulates the angiogenesis regulatory factor Angiopoietin-1

Translocation t(8;21), resulting in the AML1/ETO (AE) fusion gene is the most common cytogenetic abnormality in AML. Dysregulated angiogenesis in the bone marrow niche is predicted to have an important role in leukaemia pathogenesis. Angiopoietin-1 (ANGPT1) is a cytokine involved in haematopoietic stem cell quiescence and regulation of microvessel density within the bone marrow. ANGPT1 also has a role in transendothelial migration and is upregulated in leukemic blasts from AML patients.

In HL-60 and U937 transduced with AE, we observed an up to 280 fold increase in ANGPT1 mRNA transcript levels as measured by qRT-PCR, which correlated with an increase in secreted Angiopoietin-1 protein. Conversely, siRNA-mediated AE depletion in Kasumi-1 cells significantly decreased ANGPT1 transcript (> 99%) and protein levels.

Preliminary data suggest siRNA-targeting of ANGPT1 in Kasumi-1 decreases the invasive ability of these cells, causing a ≥50% reduction in invasion when compared to controls. This work suggests regulation of ANGPT1 by AE could have major functional consequences in the bone marrow niche and increase understanding of how the AML stem cell interacts with the niche microenvironment.