BH3 mimetic ABT-737 induces apoptosis in CD34 acute myeloid leukemia cells and shows synergistic effect with conventional chemotherapeutic drugs.

Aims: Acute myeloid leukemia (AML) is an immunophenotypically heterogenous malignant disease. The early immature CD34 AML cell subpopulation is frequently impervious to intensive chemotherapy, making them largely responsible for relapse of AML. CD34 AML cells have higher level of Bcl-2 protein expression than the CD34 subpopulation. As such, development of drugs that specifically target the Bcl-2 may have the potential to eliminate immature CD34 AML progenitor cells and provide therapeutic benefit. In this work, we made an attempt to investigate the cytotoxic effect of a novel Bcl-2 family inhibitor, ABT-737, on CD34 AML cell lines (KG1a and Kasumi-1) as well as CD34 primary AML cells.

Methods: Primary human CD34 cells were isolated from bone marrow mononuclear cells using CD34 MicroBead kit. The growth inhibitory effect was measured by cell counting kit-8. Apoptosis was analyzed by annexin V/PI assays. Protein expression was determined by Western blotting analysis.

Results: Inhibition of Bcl-2 by ABT-737 effectively inhibited growth and induced apoptosis in CD34 AML cell lines and CD34 primary AML cells without affecting CD34 normal hematopoietic cells. Furthermore, Western blot analysis showed that ABT-737 induced apoptosis associated with caspase-3 activation and poly ADP-ribose polymerase (PARP) degradation. Finally, ABT-737 synergistically enhanced the cytotoxic effect of cytarabine and daunorubicin in CD34 AML cells.

Conclusion: Taken together, these findings indicate that ABT-737 may offer as a promising molecular targeting agent in CD34 AML.