WEHI Wednesday Seminar hosted by Professor Suzanne Cory

Dr Hai Vu Nguyen

Senior Research Officer – Strasser Laboratory, Blood Cells & Blood Cancer division, WEHI

MNT: from MYC antagonist to its Achilles’ heel

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

The oncogene c-MYC regulates diverse cellular processes, including cell growth, proliferation, metabolism and, under stress conditions, apoptosis. Deregulated overexpression of MYC has been implicated in the development of most human cancers (~70%), but no inhibitor has yet been approved for clinical use, despite much effort.

MYC is the founding member of a network of related transcription factors, including MNT, which is widely expressed. MYC and MNT both bind to E-box motifs in target genes. However, whereas MYC activates transcription, MNT is a transcription repressor.

Being a MYC antagonist, MNT was expected to be a tumour suppressor. As such, MNT loss would be expected to accelerate tumorigenesis. However, using three different mouse models, we found that Mnt deletion retarded MYC-driven lymphomagenesis, and does so by enhancing apoptosis in preleukaemic lymphoid cells. Thus, MNT actually aids MYC in lymphomagenesis, by suppressing MYC-driven apoptosis.

To further clarify MNT’s role, we have also performed conditional Mnt deletion in fully malignant lymphoma cells derived from Eμ-Myc mice, which model Burkitt’s lymphoma. We found that MNT loss readily provoked apoptosis, in both p53 wt and p53 mutant tumour cells, by elevating expression of BH3-only proteins BIM and PUMA, which are major apoptosis triggers. By inhibiting apoptosis, we also found that MNT loss impaired cell cycling and increased senescence.

Importantly, MNT loss significantly enhanced the sensitivity of p53 wt and p53 mutant Eμ-Myc lymphoma cells to MCL-1 inhibitor S63845 and to chemotherapeutic agents. Furthermore, our BCL-2- overexpressing Eμ-Myc lymphoma cells, which model aggressive human ‘Double Hit Lymphomas’, had increased sensitivity to BCL-2 inhibitor ABT-199 after MNT loss. MNT deletion also improved cancer drug responses of two long-established Burkitt Lymphoma cell lines.

These results provide strong proof-of-concept for developing MNT inhibitors to improve treatment of blood cancers. In collaboration with our WEHI colleagues and the National DrugvDiscovery Centre (NDDC), we are screening “smart” chemical libraries to identify molecules that inhibit MNT from suppressing gene transcription.

All welcome!