AML Fusions Require Epigenetic Modifiers to Transform Cells

Leukemias often harbor oncogenic fusion proteins generated by chromosomal translocations. However, therapies targeting the mixed-lineage leukemia (MLL) and other fusions in acute myeloid leukemia (AML) are lacking. Protein methyltransferases (PMT) have emerged as promising targets, but their mechanisms of action remain poorly understood. Cheung and colleagues investigated the role of protein arginine methyltransferase 1 (PRMT1) in leukemia using a systematic functional screen of PRMT1 knockdown in a panel of primary cells expressing MLL and non-MLL oncogenic transcription factors. Transformation by MLL–GAS7 and MOZ–TIF2 was significantly reduced by PRMT1 knockdown, and PRMT1 expression was also required for leukemia maintenance both in vitro and in vivo. Consistent with these findings, both MLL–GAS7 and MOZ–TIF2 coimmunoprecipitated with PRMT1. PRMT1 bound to the MLL target gene locus Hoxa9, and was associated with asymmetric dimethylation of histone 4 arginine 3. PRMT1 recruitment was necessary, but not sufficient, for leukemogenesis, and a small-molecule PRMT1 inhibitor reduced the growth of MLL–GAS7 and MOZ–TIF2 xenografts and improved survival. Lysine (K)-specific demethylase 4C (KDM4C) was identified as a MOZ–TIF2-interacting protein that cooperates with PRMT1. KDM4C also interacted with MLL fusions. KDM4C recruitment enhanced Hoxa9 expression and was inversely correlated with repressive H3K9 trimethylation (H3K9me3) mark on the Hoxa9 locus. Similar to the effects of PRMT1 suppression, KDM4C knockdown or inhibition resulted in impaired transformation, reduced leukemic burden in vivo, and decreased expression of MLL target genes. RNA-sequencing analysis of MOZ–TIF2 and MLL–GAS7 cells in the presence or absence of KDM4C or PRMT1 indicated that KDM4C and PRMT1 regulate similar and largely overlapping sets of genes. Together, these findings show that the epigenetic modifiers PRMT1 and KDM4C are recruited by AML fusions, remove H3K9me3 repressive marks, and promote the transcription of AML fusion target genes, and suggest that inhibitors of these proteins warrant clinical investigation for AML treatment.

Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK, Mowen KA, et al. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 2016;29:32–48.