The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia

• DOI: 10.1038/s41375-022-01765-0
• Publication Date: 2022-11-27T01:25:02Z
• Authors: Hsiangyu Hu; Nirmalya Saha; Yuting Yang; Ejaz Ahmad; Lauren Lachowski; Uttar Shrestha; Vidhya Premkumar; James Ropa; Lili Chen; Blaine Teahan; Sierrah Grigsby; Rolf Marschalek; Zaneta Nikolovska...; Andrew G. Muntean
• Keywords: 0301 basic medicine; Oncogene Proteins, Fusion; Stem Cells; 610; Myeloid-lymphoid leukemia protein; Stem cells; Translocation, Genetic; Epigenesis, Genetic; Histones; Mice; Leukemia, Myeloid, Acute; 03 medical and health sciences; Animals; Myeloid-Lymphoid Leukemia Protein

MLL (KMT2a) translocations are found in ~10% of acute leukemia patients, giving rise to oncogenic MLL-fusion proteins. A common MLL translocation partner is ENL and associated with a poor prognosis in t(11;19) patients. ENL contains a highly conserved N-terminal YEATS domain that binds acetylated histones and interacts with the PAF1c, an epigenetic regulator protein complex essential for MLL-fusion leukemogenesis. Recently, wild-type ENL, and specifically the YEATS domain, was shown to be essential for leukemic cell growth. However, the inclusion and importance of the YEATS domain in MLL-ENL-mediated leukemogenesis remains unexplored. We found the YEATS domain is retained in 84.1% of MLL-ENL patients and crucial for MLL-ENL-mediated leukemogenesis in mouse models. Mechanistically, deletion of the YEATS domain impaired MLL-ENL fusion protein binding and decreased expression of pro-leukemic genes like Eya1 and Meis1. Point mutations that disrupt YEATS domain binding to acetylated histones decreased stem cell frequency and increased MLL-ENL-mediated leukemia latency. Therapeutically, YEATS containing MLL-ENL leukemic cells display increased sensitivity to the YEATS inhibitor SGC-iMLLT compared to control AML cells. Our results demonstrate that the YEATS domain is important for MLL-ENL fusion protein-mediated leukemogenesis and exposes an "Achilles heel" that may be therapeutically targeted for treating t(11;19) patients.