DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

Liubin Yang; Benjamin Rodriguez; Allison Mayle; Hyun Jung Park; Xueqiu Lin; Min Luo; Mira Jeong; Choladda V. Curry; Sang Bae Kim; David Ruau; Xiaotian Zhang; Ting Zhou; Michael Zhou; Vivienne I. Rebel; Grant A. Challen; Berthold Göttgens; Ju Seog Lee; Rachel Rau; Wei Li; Margaret A. Goodell

doi:10.1016/j.ccell.2016.05.003

DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

Liubin Yang, Benjamin Rodriguez, Allison Mayle, Hyun Jung Park, Xueqiu Lin, Min Luo, Mira Jeong, Choladda V. Curry, Sang Bae Kim, David Ruau, Xiaotian Zhang, Ting Zhou, Michael Zhou, Vivienne I. Rebel, Grant A. Challen, Berthold Göttgens, Ju Seog Lee, Rachel Rau, Wei Li, Margaret A. Goodell

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Abstract

DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Original language	English
Pages (from-to)	922-934
Number of pages	13
Journal	Cancer Cell
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.05.003
State	Published - Jun 13 2016

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Yang, L., Rodriguez, B., Mayle, A., Park, H. J., Lin, X., Luo, M., Jeong, M., Curry, C. V., Kim, S. B., Ruau, D., Zhang, X., Zhou, T., Zhou, M., Rebel, V. I., Challen, G. A., Göttgens, B., Lee, J. S., Rau, R., Li, W., & Goodell, M. A. (2016). DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias. Cancer Cell, 29(6), 922-934. https://doi.org/10.1016/j.ccell.2016.05.003

@article{eec101383fd84fbdbe2b920f52cab490,

title = "DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias",

abstract = "DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.",

author = "Liubin Yang and Benjamin Rodriguez and Allison Mayle and Park, {Hyun Jung} and Xueqiu Lin and Min Luo and Mira Jeong and Curry, {Choladda V.} and Kim, {Sang Bae} and David Ruau and Xiaotian Zhang and Ting Zhou and Michael Zhou and Rebel, {Vivienne I.} and Challen, {Grant A.} and Berthold G{\"o}ttgens and Lee, {Ju Seog} and Rachel Rau and Wei Li and Goodell, {Margaret A.}",

note = "Funding Information: We thank J. Licht and F. Rassool for the FLT3-ITD construct, Y. Zheng, A. Rosen, R. Nitsal, M. Landis, and K. Lin for technical support, and J. Gilbert and C. Gillespie for critical reading of the manuscript. L.Y. is funded by the Robert and Janice McNair Foundation as an MD/PhD McNair Student Scholar. This project was funded by CPRIT ( RP110028 , RP110471 and RP150292 ), the NIH ( DK092883 , CA183252 , CA193466 , and HG007538 ), the Samuel Waxman Cancer Research Foundation , and the Adrienne Helis Malvin Foundation . We also thank the Cytometry and Cell Sorting and Genomic and RNA Profiling Cores (NCI P30CA125123, P30 AI036211, P30 CA125123, and S10 RR024574) at Baylor College of Medicine. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jun,

day = "13",

doi = "10.1016/j.ccell.2016.05.003",

language = "English",

volume = "29",

pages = "922--934",

journal = "Cancer Cell",

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Yang, L, Rodriguez, B, Mayle, A, Park, HJ, Lin, X, Luo, M, Jeong, M, Curry, CV, Kim, SB, Ruau, D, Zhang, X, Zhou, T, Zhou, M, Rebel, VI, Challen, GA, Göttgens, B, Lee, JS, Rau, R, Li, W & Goodell, MA 2016, 'DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias', Cancer Cell, vol. 29, no. 6, pp. 922-934. https://doi.org/10.1016/j.ccell.2016.05.003

TY - JOUR

T1 - DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

AU - Yang, Liubin

AU - Rodriguez, Benjamin

AU - Mayle, Allison

AU - Park, Hyun Jung

AU - Lin, Xueqiu

AU - Luo, Min

AU - Jeong, Mira

AU - Curry, Choladda V.

AU - Kim, Sang Bae

AU - Ruau, David

AU - Zhang, Xiaotian

AU - Zhou, Ting

AU - Zhou, Michael

AU - Rebel, Vivienne I.

AU - Challen, Grant A.

AU - Göttgens, Berthold

AU - Lee, Ju Seog

AU - Rau, Rachel

AU - Li, Wei

AU - Goodell, Margaret A.

N1 - Funding Information: We thank J. Licht and F. Rassool for the FLT3-ITD construct, Y. Zheng, A. Rosen, R. Nitsal, M. Landis, and K. Lin for technical support, and J. Gilbert and C. Gillespie for critical reading of the manuscript. L.Y. is funded by the Robert and Janice McNair Foundation as an MD/PhD McNair Student Scholar. This project was funded by CPRIT ( RP110028 , RP110471 and RP150292 ), the NIH ( DK092883 , CA183252 , CA193466 , and HG007538 ), the Samuel Waxman Cancer Research Foundation , and the Adrienne Helis Malvin Foundation . We also thank the Cytometry and Cell Sorting and Genomic and RNA Profiling Cores (NCI P30CA125123, P30 AI036211, P30 CA125123, and S10 RR024574) at Baylor College of Medicine. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/6/13

Y1 - 2016/6/13

N2 - DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

AB - DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

UR - http://www.scopus.com/inward/record.url?scp=84979528611&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.05.003

DO - 10.1016/j.ccell.2016.05.003

M3 - Article

C2 - 27300438

AN - SCOPUS:84979528611

SN - 1535-6108

VL - 29

SP - 922

EP - 934

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

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