Antiapoptotic BCL2 family proteins BCL-XL and MCL1 as factors predicting resistance against venetoclax plus azacitidine for patients with newly diagnosed acute myelogenous leukemia

The combination of Venetoclax (VEN), a BCL2 inhibitor, and Azacitidine (AZA), a hypomethylating agent, is the standard treatment for acute myelogenous leukemia (AML) in patients older than 65 years who are not eligible for intensive chemotherapy. While high response rates for this treatment have been noted, it has been also reported that the anti-apoptotic BCL2 family proteins BCL-XL and MCL1 may be involved in VEN resistance. However, no study has heretofore been conducted to investigate the effectiveness of treatment and the expression of BCL-XL or MCL1 in patients treated with VEN + AZA therapy. In this study, we analyzed blasts from patients with newly diagnosed AML treated with VEN + AZA therapy by qPCR, confirmed by siRNA in cultured cell lines, and evaluated the validity of the immunostaining method. We demonstrated that BCL-XL or MCL1 was highly expressed in leukemia cells of patients who did not respond to this treatment. In addition, leukemia cells from patients who had responded to VEN + AZA but relapsed during the course of treatment showed increased expression of BCL-XL or MCL1 compared to pre-treatment levels. Furthermore, downregulation of BCL-XL expression in a VEN-resistant AML cell line with siRNA increased sensitivity to VEN. On the other hand, the expression of BCL-XL and MCL1 in leukemia cells could be easily semi-quantified by immunostaining, with these results correlating with those obtained by qPCR. These results indicate that immunostaining for BCL-XL and MCL1 upon bone marrow examination at diagnosis not only can predict susceptibility to VEN + AZA therapy, but may also be useful for patient stratification for VEN + AZA treatment in the future.