Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.
Grebien F., Vedadi M., Getlik M., Giambruno R., Grover A., Avellino R., Skucha A., Vittori S., Kuznetsova E., Smil D., Barsyte-Lovejoy D., Li F., Poda G., Schapira M., Wu H., Dong A., Senisterra G., Stukalov A., Huber KVM., Schönegger A., Marcellus R., Bilban M., Bock C., Brown PJ., Zuber J., Bennett KL., Al-Awar R., Delwel R., Nerlov C., Arrowsmith CH., Superti-Furga G.
The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.