ENL binds acetylated histone 3 to promote oncogenic gene expression and AML cell proliferation.
Major finding: ENL binds acetylated histone 3 to promote oncogenic gene expression and AML cell proliferation.
Mechanism: ENL loss prevents Pol II recruitment and reduces transcriptional initiation and elongation.
Impact: Pharmacologic disruption of ENL chromatin binding may be beneficial in patients with AML.
Acute myeloid leukemia (AML) is often driven by chromosomal translocations that fuse MLL1 to either of the YEATS domain–containing proteins ENL or AF9, and MLL fusions are associated with aggressive disease and poor outcomes. The YEATS domain binds to acetyl-lysines, but its functional role in leukemia remains unclear. In related studies, Wan, Wen, Li, and colleagues and Erb and colleagues found that CRISPR/Cas9-mediated deletion of ENL, but not AF9, reduced the growth of MLL-rearranged and non–MLL-rearranged leukemia cells. In vivo, ENL depletion reduced leukemia growth and extended survival, altogether indicating that ENL expression is required for AML maintenance. RNA sequencing revealed that ENL depletion resulted in downregulation of leukemic drivers including HOXA10, MYC, MYB, and MEIS1, and upregulation of the myeloid differentiation marker ITGAM. Moreover, ENL loss resulted in upregulation of the myeloid lineage differentiation signature and downregulation of the leukemic stem cell and MYC-associated gene signatures. Chromatin immunoprecipitation sequencing found that ENL was enriched at promoters bound by RNA polymerase II (Pol II) and associated with acetylated histone 3 lysine 27 (H3K27ac) and H3K9ac. Mechanistically, the YEATS domain of ENL bound to acetylated histone H3 to facilitate Pol II recruitment and promote transcriptional initiation and elongation of ENL target genes required for AML maintenance. This suggests the possibility for therapies targeting the interaction between ENL and acetylated histones. Like the acetyl-lysine reader protein BRD4, ENL interacted with Pol II and P-TEFb, and thus might cooperate with BRD4. Indeed, Wan, Wen, Li, and colleagues found that ENL depletion sensitized cells to BRD4 inhibition with the BET inhibitor JQ1. The finding that ENL chromatin binding is required for AML maintenance suggests that therapies aimed at disrupting the YEATS domain may be beneficial in patients with AML, alone or in combination with BET inhibitors.
Wan L, Wen H, Li Y, Lyu J, Xi Y, Hoshii T, et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 2017;543:265–9.