TET1 is a tumor suppressor of hematopoietic malignancy

Luisa Cimmino; Meelad M. Dawlaty; Delphine Ndiaye-Lobry; Yoon Sing Yap; Sofia Bakogianni; Yiting Yu; Sanchari Bhattacharyya; Rita Shaknovich; Huimin Geng; Camille Lobry; Jasper Mullenders; Bryan King; Thomas Trimarchi; Beatriz Aranda-Orgilles; Cynthia Liu; Steven Shen; Amit K. Verma; Rudolf Jaenisch; Iannis Aifantis

doi:10.1038/ni.3148

TET1 is a tumor suppressor of hematopoietic malignancy

Luisa Cimmino, Meelad M. Dawlaty, Delphine Ndiaye-Lobry, Yoon Sing Yap, Sofia Bakogianni, Yiting Yu, Sanchari Bhattacharyya, Rita Shaknovich, Huimin Geng, Camille Lobry, Jasper Mullenders, Bryan King, Thomas Trimarchi, Beatriz Aranda-Orgilles, Cynthia Liu, Steven Shen, Amit K. Verma, Rudolf Jaenisch, Iannis Aifantis

Research output: Contribution to journal › Article › peer-review

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Abstract

The methylcytosine dioxygenase TET1 ("ten-eleven translocation 1") is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.

Original language	English (US)
Pages (from-to)	653-662
Number of pages	10
Journal	Nature immunology
Volume	16
Issue number	6
DOIs	https://doi.org/10.1038/ni.3148
State	Published - May 19 2015
Externally published	Yes

Bibliographical note

Funding Information:
We thank members of the Aifantis laboratory for discussions; M. Xu and F. Yang for help and advice; L. Pasqualucci (Columbia University) for control antibodies and control tissue sections for immunohistochemistry of mouse B cell lymphomas and expertise; K. Ganz, R. Flannery, D. Fu and T. Adil for help with animal husbandry and tissue collection; A. Heguy and I. Dolgalev for assistance with microarray experiments, RNA-seq and exome sequencing; the NYU Flow Cytometry facility for cell sorting; the NYU Histology Core; and E. Oricchio for assistance with analysis of data from patients with FL. Supported by the Damon Runyon Cancer Research Foundation (M.M.D.), the US National Institutes of Health (5RO1HD045022 and 5R37CA084198 for work in the laboratory of R.J.; and 1R01CA169784, 1R01CA133379, 1R01CA105129, 1R01CA149655 and 5R01CA173636 for the Aifantis laboratory), the Simons Foundation (for work in the laboratory of R.J.), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, the Alex’s Lemonade Stand Foundation for Childhood Cancer, the St. Baldrick’s Cancer Research Foundation, the National Health and Medical Research Council (L.C.) and the Howard Hughes Medical Institute (I.A.).

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Cimmino, L., Dawlaty, M. M., Ndiaye-Lobry, D., Yap, Y. S., Bakogianni, S., Yu, Y., Bhattacharyya, S., Shaknovich, R., Geng, H., Lobry, C., Mullenders, J., King, B., Trimarchi, T., Aranda-Orgilles, B., Liu, C., Shen, S., Verma, A. K., Jaenisch, R., & Aifantis, I. (2015). TET1 is a tumor suppressor of hematopoietic malignancy. Nature immunology, 16(6), 653-662. https://doi.org/10.1038/ni.3148

Cimmino, L, Dawlaty, MM, Ndiaye-Lobry, D, Yap, YS, Bakogianni, S, Yu, Y, Bhattacharyya, S, Shaknovich, R, Geng, H, Lobry, C, Mullenders, J, King, B, Trimarchi, T, Aranda-Orgilles, B, Liu, C, Shen, S, Verma, AK, Jaenisch, R & Aifantis, I 2015, 'TET1 is a tumor suppressor of hematopoietic malignancy', Nature immunology, vol. 16, no. 6, pp. 653-662. https://doi.org/10.1038/ni.3148

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abstract = "The methylcytosine dioxygenase TET1 ({"}ten-eleven translocation 1{"}) is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.",

author = "Luisa Cimmino and Dawlaty, {Meelad M.} and Delphine Ndiaye-Lobry and Yap, {Yoon Sing} and Sofia Bakogianni and Yiting Yu and Sanchari Bhattacharyya and Rita Shaknovich and Huimin Geng and Camille Lobry and Jasper Mullenders and Bryan King and Thomas Trimarchi and Beatriz Aranda-Orgilles and Cynthia Liu and Steven Shen and Verma, {Amit K.} and Rudolf Jaenisch and Iannis Aifantis",

note = "Funding Information: We thank members of the Aifantis laboratory for discussions; M. Xu and F. Yang for help and advice; L. Pasqualucci (Columbia University) for control antibodies and control tissue sections for immunohistochemistry of mouse B cell lymphomas and expertise; K. Ganz, R. Flannery, D. Fu and T. Adil for help with animal husbandry and tissue collection; A. Heguy and I. Dolgalev for assistance with microarray experiments, RNA-seq and exome sequencing; the NYU Flow Cytometry facility for cell sorting; the NYU Histology Core; and E. Oricchio for assistance with analysis of data from patients with FL. Supported by the Damon Runyon Cancer Research Foundation (M.M.D.), the US National Institutes of Health (5RO1HD045022 and 5R37CA084198 for work in the laboratory of R.J.; and 1R01CA169784, 1R01CA133379, 1R01CA105129, 1R01CA149655 and 5R01CA173636 for the Aifantis laboratory), the Simons Foundation (for work in the laboratory of R.J.), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, the Alex{\textquoteright}s Lemonade Stand Foundation for Childhood Cancer, the St. Baldrick{\textquoteright}s Cancer Research Foundation, the National Health and Medical Research Council (L.C.) and the Howard Hughes Medical Institute (I.A.).",

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AU - Cimmino, Luisa

AU - Dawlaty, Meelad M.

AU - Ndiaye-Lobry, Delphine

AU - Yap, Yoon Sing

AU - Bakogianni, Sofia

AU - Yu, Yiting

AU - Bhattacharyya, Sanchari

AU - Shaknovich, Rita

AU - Geng, Huimin

AU - Lobry, Camille

AU - Mullenders, Jasper

AU - King, Bryan

AU - Trimarchi, Thomas

AU - Aranda-Orgilles, Beatriz

AU - Liu, Cynthia

AU - Shen, Steven

AU - Verma, Amit K.

AU - Jaenisch, Rudolf

AU - Aifantis, Iannis

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TET1 is a tumor suppressor of hematopoietic malignancy

Abstract

Bibliographical note

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