Axin-2/BCL2 axis regulates apoptosis upon targeting TAM kinase

Leukemia is the clonal expansion of abnormal undifferentiated white blood cells which outnumber the normal cells causing severe platelet and red blood cells (RBCs) depletion. The overexpression of TAM (Tyro3, Axl and MerTk) Kinase receptors has been associated with leukemogenesis. The expression of TAM Kinase receptors has been known in the representative leukemic cell lines selected for this study. This study was undertaken to investigate the link between downstream effectors of canonical WNT, PI3K/AKT, RAS/MAPK/ERK and intrinsic apoptotic pathway to propose a targeted therapy for leukemia. Proliferation assay carried out at concentrations 2× (0.3, 0.5, 1, 1.5µM) of TAM Kinase receptor inhibitors revealed marked proliferation inhibition in acute myeloid leukemia (AML) in comparison to chronic myeloid and acute lymphocytic leukemia. The transcriptional analysis with two-step real time PCR and translational analysis via western blotting highlighted Axin-2/BCL2 axis to be active behind the mitochondrial apoptosis. Our findings show that upon targeting TAM Kinase receptors Axin2 and BCL2 expression changed contrariwise reflecting a potential canonical WNT involvement in mitochondrial apoptosis. A high Axin-2 and low BCL2 in Kasumi-1 and a low Axin-2 with a high BCL2 in K562 and Jurkat supports the aforementioned WNT involvement in intrinsic apoptotic signaling. A high BCl2 might have induced cell cycle arrest in Molm-13. A comparative analysis of the study strengthened the notion that resistance and induction of proliferation inhibition in leukemic cell lines depends upon the Axin-2/BCL2 axis upon targeted TAM kinase receptor inhibition. Therefore, breaking this axis can be proposed to prevent resistance in chronic myeloid and acute lymphoid leukemia.