Reading the future of leukaemia

The identification of the regulatory protein ENL as essential to an aggressive form of leukaemia provides insight into transcriptional regulation and highlights potential avenues for therapy. See Letters p.265 & p.270 Cancer cells often exploit transcription machinery and chromatin regulatory pathways to activate oncogenic gene expression programs. Chromatin regulatory mechanisms such as the recognition of modified histones by 'reader' proteins are therefore being explored as potential therapeutic targets in cancer. Here, Xiaobing Shi and colleagues show that ENL is a chromatin reader protein that regulates oncogenic programs in acute myeloid leukaemia (AML). It binds via its YEATS domain to acetylated histones on the promoters of actively transcribed genes and links to the transcriptional machinery. Depletion of ENL leads to anti-leukaemic effects, indicating that disrupting the interaction between the ENL YEATS domain and acetylated histones could be a potential therapeutic approach for AML, either alone or in combination with BET inhibitors. A related paper in this week's issue of Nature from James Bradner and colleagues provides further insights into the role of ENL in leukaemia. Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene give rise to acute myeloid leukaemia (AML). Here, James Bradner and colleagues perform a genome-scale loss-of-function screen using CRISPR–Cas9 technology in MLL-AF4 AML cells. They find that the ENL gene is critical for cell proliferation and use a chemical genetic strategy of targeted protein degradation to show that loss of ENL suppresses transcriptional activation as well as leukaemic growth. ENL-dependent leukaemic growth depends on its YEATS chromatin reader domain, indicating that competitive antagonists of the YEATS domain could be potential therapeutics for AML. A related paper in this week's issue of Nature from Xiaobing Shi and colleagues provides insights into the function of the ENL YEATS domain in recognizing acetylated histones.