TY - JOUR
T1 - The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia
AU - Hu, Hsiangyu
AU - Saha, Nirmalya
AU - Yang, Yuting
AU - Ahmad, Ejaz
AU - Lachowski, Lauren
AU - Shrestha, Uttar
AU - Premkumar, Vidhya
AU - Ropa, James
AU - Chen, Lili
AU - Teahan, Blaine
AU - Grigsby, Sierrah
AU - Marschalek, Rolf
AU - Nikolovska-Coleska, Zaneta
AU - Muntean, Andrew G.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142488672&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01765-0
DO - 10.1038/s41375-022-01765-0
M3 - Article
AN - SCOPUS:85142488672
SN - 0887-6924
VL - 37
SP - 190
EP - 201
JO - Leukemia
JF - Leukemia
IS - 1
ER -