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Targeting AML MCL-1 re-sensitizes BCL-2 inhibition
MCL-1 mediates venetoclax resistance, and its inhibition sensitizes acute myeloid leukemia cell lines to BCL-2 inhibition
Molm13 and MV4-11 cells are relatively sensitive, whereas OCI-AML3 cells are resistant, to venetoclax (Online Supplementary Figure S2A). Acquired venetoclax- resistant AML cell lines have increased MCL-1, but they likely also have altered levels of many other proteins. In order to determine whether MCL-1 played a key role in venetoclax resistance and whether co-targeting BCL-2 and MCL-1 overcomes this resistance, we treated MCL-
A
1-KD OCI-AML3 and MCL-1-OE Molm13 and MV4-11 cells with venetoclax or AZD5991. Whereas MCL-1-KD greatly sensitized OCI-AML3 cells to venetoclax (Figure 3A), MCL-1-OE Molm13 (Figure 3B) and MV4-11 cells (Online Supplementary Figure S2B) were largely insensitive to the drug. Responses to AZD5991 were similar, though to a lesser degree (Figure 3A and B; Online Supplementary Figure S2B). We then treated OCI-AML3 and MCL-1-OE Molm13 and MV4-11 cells with venetoclax plus AZD5991. The combination synergistically induced apoptosis and decreased viable cells in the intrinsically
B
Figure 3. Continued on following page.
haematologica | 2022; 107(1)
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