Acute myeloid leukaemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens we identified
IKZF1
/IKAROS as an essential transcription factor in MLL1-rearranged (
MLL
-
r
) AML that maintains leukaemogenic gene expression while also repressing pathways for tumour suppression, immune regulation, and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with MLL1/MENIN and MEIS1 and an extensive hematopoietic transcriptional complex involving HOXA10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukaemogenic transcriptional networks resulting in synergistic killing of leukaemia cells and providing a paradigm for improved drug-targeting of transcription, and an opportunity for rapid clinical translation.