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 Neilly; Rudolf Jaenisch; Feng Chun Yang; James C. Mulloy; Peng Jin; Paul P. Liu; Janet D. Rowley; Mingjiang Xu; Chuan He; Jianjun Chen

doi:10.1073/pnas.1310656110

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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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 language	English (US)
Pages (from-to)	11994-11999
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	29
DOIs	https://doi.org/10.1073/pnas.1310656110
State	Published - Jul 16 2013
Externally published	Yes

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10.1073/pnas.1310656110

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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

Huang, H, Jiang, X, Li, Z, Li, Y, Song, CX, He, C, Sun, M, Chen, P, Gurbuxani, S, Wang, J, Hong, GM, Elkahloun, AG, Arnovitz, S, Wang, J, Szulwach, K, Lin, L, Street, C, Wunderlich, M, Dawlaty, M, Neilly, MB, Jaenisch, R, Yang, FC, Mulloy, JC, Jin, P, Liu, PP, Rowley, JD, Xu, M, He, C & 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, vol. 110, no. 29, pp. 11994-11999. https://doi.org/10.1073/pnas.1310656110

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title = "TET1 plays an essential oncogenic role in MLL-rearranged leukemia",

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.",

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

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T1 - TET1 plays an essential oncogenic role in MLL-rearranged leukemia

AU - Huang, Hao

AU - Jiang, Xi

AU - Li, Zejuan

AU - Li, Yuanyuan

AU - Song, Chun Xiao

AU - He, Chunjiang

AU - Sun, Miao

AU - Chen, Ping

AU - Gurbuxani, Sandeep

AU - Wang, Jiapeng

AU - Hong, Gia Ming

AU - Elkahloun, Abdel G.

AU - Arnovitz, Stephen

AU - Wang, Jinhua

AU - Szulwach, Keith

AU - Lin, Li

AU - Street, Craig

AU - Wunderlich, Mark

AU - Dawlaty, Meelad

AU - Neilly, Mary Beth

AU - Jaenisch, Rudolf

AU - Yang, Feng Chun

AU - Mulloy, James C.

AU - Jin, Peng

AU - Liu, Paul P.

AU - Rowley, Janet D.

AU - Xu, Mingjiang

AU - He, Chuan

AU - Chen, Jianjun

PY - 2013/7/16

Y1 - 2013/7/16

N2 - 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.

AB - 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.

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

TET1 plays an essential oncogenic role in MLL-rearranged leukemia

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