TET1 plays an essential oncogenic role in MLL-rearranged leukemia

• Type of Material: Article
• Authors: Hao Huang, University of Chicago; Xi Jiang, University of Chicago; Zejuan Li, University of Chicago; Yuanyuan Li, University of Chicago; Chun-Xiao Song, University of Chicago; Chunjiang He, University of Chicago; Miao Sun, Genomics and Systems Biology; Ping Chen, University of Chicago; Sandeep Gurbuxani, University of Chicago; Jiapeng Wang, Indiana University; Gia-Ming Hong, University of Chicago; Abdel G. Elkahloun, National Human Genome Research Institute; Stephen Arnovitz, University of Chicago; Jinhua Wang, University of Chicago; Keith Szulwach, Emory University; Li Lin, Emory University; Craig Street, Emory University; Mark Wunderlich, University of Cincinnati; Meelad Dawlaty, Massachusetts Institute of Technology; Mary Beth Neilly, University of Chicago; Rudolf Jaenisch, Massachusetts Institute of Technology; Feng-Chun Yang, Indiana University; James C. Mulloy, University of Cincinnati; Peng Jin, Emory University; Paul P. Liu, National Human Genome Research Institute; Janet D. Rowley, University of Chicago; Mingjiang Xu, Indiana University; Chuan He, University of Chicago; Jianjun Chen, University of Chicago
• Language: English
• Date: 2013-07-16
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2013 PNAS
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1310656110
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 110
• Issue: 29
• Start Page: 11994
• End Page: 11999
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants CA127277 (to J.C.), NS079625 and HD073162 (to P.J.), HG006827 (to Chuan He), HL112294 (to M.X.), and CA118319 (to J.C.M.), the Intramural Program of the National Human Genome Research Institute (A.G.E. and P.P.L.), the American Cancer Society Research Scholar grant (J.C.), the Emory Genetics Discovery Fund (P.J.), a Winship Cancer Institute Kennedy Seed Grant and a Winship Multi-Investigator Pilot Grant (to P.J.), the G. Harold and Leila Y. Mathers Charitable Foundation (J.C.), Gabrielle’s Angel Foundation (J.C., Z.L., H.H., X.J., and G.-M.H.), a Leukemia and Lymphoma Society (LLS) Translational Research grant (to J.D.R. and J.C.), an LLS Special Fellowship (to Z.L.), and the University of Chicago Committee on Cancer Biology Fellowship Program (X.J.).; M.S. was supported by Department of Defense Predoctoral Traineeship Award W81XWH-10-1-0396.; J.C.M. is an LLS Scholar.
• Keywords: Science & Technology - Other Topics; EMBRYONIC STEM-CELLS; 5-HYDROXYMETHYLCYTOSINE; GENE-EXPRESSION; MAMMALIAN DNA; Science & Technology; MIXED-LINEAGE LEUKEMIA; HEMATOPOIETIC-CELLS; Multidisciplinary Sciences; SELF-RENEWAL; DOWN-REGULATION; ACUTE MYELOID-LEUKEMIA; POSTNATAL-DEVELOPMENT

Abstract

The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent downregulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/ Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.