DISORDERED HISTONE METHYLATION IN HEMATOLOGICAL MALIGNANCIES THE CASE OF UTX/KDM6A

Alterations of epigenetic proteins that modulate the gene repressive lysine 27 on histone H3 (H3K27me) are recurrent features in cancers, including multiple myeloma (MM). The histone demethylase UTX/KDM6A, mutated in up to 10% of cases of MM activates genes by removing the H3K27me3 repressive histone mark, counteracting EZH2. RNA-sequencing studies showed that UTX upregulated genes in association with loss of H3K27me. Treatment of MM cell lines with an EZH2 inhibitor preferentially slowed growth of UTX-null cells. EZH2 inhibitors activated many of the same genes as UTX but also induced the earlier stage B cell marker Bcl6 which, in turn, shut off the late B cell IRF4 and MYC, leading to cell death.