Our previous mouse genetic studies showed that loss of the transcription repressor MNT enhanced apoptosis of premalignant lymphoid cells over-expressing MYC and inhibited lymphoma development. Here, we have explored the consequences of inducing Mnt deletion in fully malignant lymphoma cells. MNT loss provoked apoptosis of p53 wt and, albeit more slowly, p53 mutant Eμ-Myc lymphoma cells, preceded by elevated levels of major BH3-only proteins BIM and PUMA. By inhibiting apoptosis, we showed that MNT loss also impaired cell cycling and increased senescence. Eμ-Myc lymphoma cells depend on the BCL-2 ortholog MCL-1 for survival and expansion and, importantly, MNT loss enhanced their sensitivity to the MCL-1 inhibitor S63845 and to several chemotherapeutic agents. In BCL-2-overexpressing Eμ-Myc lymphoma cells, which model aggressive human ‘Double Hit Lymphomas’, MNT loss enhanced sensitivity to the BCL-2 inhibitor ABT-199, even after BAX loss. Furthermore, MNT deletion improved drug responses of two long-established Burkitt Lymphoma cell lines.
SIGNIFICANCE
This study establishing the MNT dependency of Eμ-Myc lymphoma cells and demonstrating that MNT loss enhances their sensitivity to apoptosis induced by conventional chemotherapeutics and BH3 mimetic drugs provides strong proof-of-concept for developing MNT inhibitors to improve treatment of MYC-driven blood cancers.