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DOI: 10.1055/s-0040-1709776
Testing ABT-263 for the treatment of pediatric acute myeloid leukemia
Deregulation of the anti-apoptotic members of the BCL-2 family is a well-known tumor evasion strategy. Consequently, a drastic decrease of leukemic burden can be achieved by genetic knockdown or pharmacologic inhibition of the BCL-2 family members. Here, we evaluated the potential of the BCL-2/-XL inhibitor ABT-263 (Navitoclax) as a therapeutic option. Various AML cell lines as well as leukemic blasts from AML patients were subjected to increasing concentrations of ABT-263 in vitro. Human peripheral blood derived CD34+ cells served as control. A patient-derived-xenograft (PDX) model in immunocompromised MISTRG and NSG mice was subsequently used to examine the in vivo response. Mixed lineage leukemic blasts (MLL) and cell lines exhibited clear antiproliferative response. Subsequent testing in PDX models further highlighted this effect and showed a survival benefit for MLL in vivo. We observed a strong correlation between survival benefit and BCL-2 – but not BCL-XL expression. Our findings emphasize the importance of the corresponding pathway in the maintenance and progression of MLL-rearranged AML and give an outlook towards unexplored targeted therapeutic opportunities.
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Publication History
Article published online:
13 May 2020
© Georg Thieme Verlag KG
Stuttgart · New York