Establishment of new therapeutic options for the treatment of Myeloid Leukemia in Down syndrome (ML-DS)

Children with DS have a 400-fold increased risk of developing myeloid leukemia (ML-DS). Although ML-DS has a good prognosis, children with DS particularly suffer from the side effects of polychemotherapy. Hence, there is an urgent need for the development of new, more sustainable therapeutic agents. Expression studies and ML-DS modeling in mice revealed high expression of antiapoptotic BCL2-family member BCL-XL as well as derepression of Lysine-specific demethylase 1A (LSD1) target genes. Therefore, BCL inhibitor ABT-263 (Navitoclax) and LSD1 inhibitors (iLSD1) present as promising drug candidates against ML-DS. Various AML cell lines as well as leukemic blasts form AML patients were subjected to serially diluted concentrations of ABT-263 and iLSD1 in vitro, CD34+ cells served as control. Of note, ML-DS leukemic blasts and cell lines exhibited clear antiproliferative response with IC50 values of 362 nM and 33 nM, whereas for CD34+ cells the IC50 was not achieved. The effectiveness of Navitoclax and iLSD1 highlight the importance of the corresponding pathways in the maintenance and progression of ML-DS and give an outlook towards unexplored targeted therapeutic opportunities.