Acute myeloid leukaemia (AML) is a haematological malignancy characterised by an over-production of immature myeloid cells. Rearrangements of the Mixed Lineage Leukaemia (MLL) gene result in an aggressive subtype of AML (MLL-r AML). MLL fusion proteins associate with several cofactors, including Menin and DOT1L to drive this disease.
Targeted therapies have been developed that block these interactions. Menin inhibitors, in particular, have shown great promise with 30% remission achieved in a heavily pre-treated population in phase I clinical trials.
However, early evidence suggests that MLL-r leukaemias develop resistance to this treatment. Therefore, understanding the potential adaptive mechanisms to Menin inhibition in leukaemia cells is crucial in order to improve the clinical utility of this promising therapy.
In this project we have developed models of acquired Menin inhibition therapy resistance. In these models we have characterised the genetic, epigenetic and transcriptional changes that occur. This work elucidates the mechanisms of resistance and may inform the therapeutic options for patients with MLL-r AML.