TET1 plays an essential oncogenic role in MLL-rearranged leukemia

Hao Huang, Xi Jiang, Zejuan Li, Yuanyuan Li, Chun Xiao Song, Chunjiang He, Miao Sun, Ping Chen, Sandeep Gurbuxani, Jiapeng Wang, Gia Ming Hong, Abdel G. Elkahloun, Stephen Arnovitz, Jinhua Wang, Keith Szulwach, Li Lin, Craig Street, Mark Wunderlich, Meelad Dawlaty, Mary Beth NeillyRudolf Jaenisch, Feng Chun Yang, James C. Mulloy, Peng Jin, Paul P. Liu, Janet D. Rowley, Mingjiang Xu, Chuan He, Jianjun Chen

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122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11994-11999
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number29
DOIs
StatePublished - Jul 16 2013

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    Huang, H., Jiang, X., Li, Z., Li, Y., Song, C. X., He, C., Sun, M., Chen, P., Gurbuxani, S., Wang, J., Hong, G. M., Elkahloun, A. G., Arnovitz, S., Wang, J., Szulwach, K., Lin, L., Street, C., Wunderlich, M., Dawlaty, M., ... Chen, J. (2013). TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 11994-11999. https://doi.org/10.1073/pnas.1310656110