Cooperative Epigenetic Modulation by Cancer Amplicon Genes

Lixin Rui; N. C.Tolga Emre; Michael J. Kruhlak; Hye Jung Chung; Christian Steidl; Graham Slack; George W. Wright; Georg Lenz; Vu N. Ngo; Arthur L. Shaffer; Weihong Xu; Hong Zhao; Yandan Yang; Laurence Lamy; R. Eric Davis; Wenming Xiao; John Powell; David Maloney; Craig J. Thomas; Peter Möller; Andreas Rosenwald; German Ott; Hans Konrad Muller-Hermelink; Kerry Savage; Joseph M. Connors; Lisa M. Rimsza; Elias Campo; Elaine S. Jaffe; Jan Delabie; Erlend B. Smeland; Dennis D. Weisenburger; Wing C. Chan; Randy D. Gascoyne; David Levens; Louis M. Staudt

doi:10.1016/j.ccr.2010.11.013

Cooperative Epigenetic Modulation by Cancer Amplicon Genes

Lixin Rui, N. C.Tolga Emre, Michael J. Kruhlak, Hye Jung Chung, Christian Steidl, Graham Slack, George W. Wright, Georg Lenz, Vu N. Ngo, Arthur L. Shaffer, Weihong Xu, Hong Zhao, Yandan Yang, Laurence Lamy, R. Eric Davis, Wenming Xiao, John Powell, David Maloney, Craig J. Thomas, Peter MöllerAndreas Rosenwald, German Ott, Hans Konrad Muller-Hermelink, Kerry Savage, Joseph M. Connors, Lisa M. Rimsza, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Dennis D. Weisenburger, Wing C. Chan, Randy D. Gascoyne, David Levens, Louis M. Staudt

Laboratory Medicine and Pathology

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

221 Scopus citations

Abstract

Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.

Original language	English (US)
Pages (from-to)	590-605
Number of pages	16
Journal	Cancer cell
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2010.11.013
State	Published - Dec 14 2010

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2010.11.013

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Rui, L., Emre, N. C. T., Kruhlak, M. J., Chung, H. J., Steidl, C., Slack, G., Wright, G. W., Lenz, G., Ngo, V. N., Shaffer, A. L., Xu, W., Zhao, H., Yang, Y., Lamy, L., Davis, R. E., Xiao, W., Powell, J., Maloney, D., Thomas, C. J., ... Staudt, L. M. (2010). Cooperative Epigenetic Modulation by Cancer Amplicon Genes. Cancer cell, 18(6), 590-605. https://doi.org/10.1016/j.ccr.2010.11.013

Rui, L, Emre, NCT, Kruhlak, MJ, Chung, HJ, Steidl, C, Slack, G, Wright, GW, Lenz, G, Ngo, VN, Shaffer, AL, Xu, W, Zhao, H, Yang, Y, Lamy, L, Davis, RE, Xiao, W, Powell, J, Maloney, D, Thomas, CJ, Möller, P, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Savage, K, Connors, JM, Rimsza, LM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Weisenburger, DD, Chan, WC, Gascoyne, RD, Levens, D & Staudt, LM 2010, 'Cooperative Epigenetic Modulation by Cancer Amplicon Genes', Cancer cell, vol. 18, no. 6, pp. 590-605. https://doi.org/10.1016/j.ccr.2010.11.013

@article{930c73731eee4affb81f816da593ede6,

title = "Cooperative Epigenetic Modulation by Cancer Amplicon Genes",

abstract = "Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.",

author = "Lixin Rui and Emre, {N. C.Tolga} and Kruhlak, {Michael J.} and Chung, {Hye Jung} and Christian Steidl and Graham Slack and Wright, {George W.} and Georg Lenz and Ngo, {Vu N.} and Shaffer, {Arthur L.} and Weihong Xu and Hong Zhao and Yandan Yang and Laurence Lamy and Davis, {R. Eric} and Wenming Xiao and John Powell and David Maloney and Thomas, {Craig J.} and Peter M{\"o}ller and Andreas Rosenwald and German Ott and Muller-Hermelink, {Hans Konrad} and Kerry Savage and Connors, {Joseph M.} and Rimsza, {Lisa M.} and Elias Campo and Jaffe, {Elaine S.} and Jan Delabie and Smeland, {Erlend B.} and Weisenburger, {Dennis D.} and Chan, {Wing C.} and Gascoyne, {Randy D.} and David Levens and Staudt, {Louis M.}",

note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and an NCI SPECS grant (UO1-CA 114778). L.R. is the recipient of a C.J. Martin Fellowship from the National Health and Medical Research Council (NHMRC) of Australia. G.L. was also supported by a research grant from the German Research Foundation (DFG). C.S. is funded by a fellowship award from the Cancer Research Society of Canada. R.D.G. is funded by a Terry Fox Foundation award (019001) and a Canadian Institutes for Health Research grant (178536). We thank Dennis Huszar of AstraZeneca for providing AZD1480. ",

year = "2010",

month = dec,

day = "14",

doi = "10.1016/j.ccr.2010.11.013",

language = "English (US)",

volume = "18",

pages = "590--605",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

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TY - JOUR

T1 - Cooperative Epigenetic Modulation by Cancer Amplicon Genes

AU - Rui, Lixin

AU - Emre, N. C.Tolga

AU - Kruhlak, Michael J.

AU - Chung, Hye Jung

AU - Steidl, Christian

AU - Slack, Graham

AU - Wright, George W.

AU - Lenz, Georg

AU - Ngo, Vu N.

AU - Shaffer, Arthur L.

AU - Xu, Weihong

AU - Zhao, Hong

AU - Yang, Yandan

AU - Lamy, Laurence

AU - Davis, R. Eric

AU - Xiao, Wenming

AU - Powell, John

AU - Maloney, David

AU - Thomas, Craig J.

AU - Möller, Peter

AU - Rosenwald, Andreas

AU - Ott, German

AU - Muller-Hermelink, Hans Konrad

AU - Savage, Kerry

AU - Connors, Joseph M.

AU - Rimsza, Lisa M.

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Weisenburger, Dennis D.

AU - Chan, Wing C.

AU - Gascoyne, Randy D.

AU - Levens, David

AU - Staudt, Louis M.

N1 - Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and an NCI SPECS grant (UO1-CA 114778). L.R. is the recipient of a C.J. Martin Fellowship from the National Health and Medical Research Council (NHMRC) of Australia. G.L. was also supported by a research grant from the German Research Foundation (DFG). C.S. is funded by a fellowship award from the Cancer Research Society of Canada. R.D.G. is funded by a Terry Fox Foundation award (019001) and a Canadian Institutes for Health Research grant (178536). We thank Dennis Huszar of AstraZeneca for providing AZD1480.

PY - 2010/12/14

Y1 - 2010/12/14

N2 - Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.

AB - Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.

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U2 - 10.1016/j.ccr.2010.11.013

DO - 10.1016/j.ccr.2010.11.013

M3 - Article

C2 - 21156283

AN - SCOPUS:78650012116

SN - 1535-6108

VL - 18

SP - 590

EP - 605

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

Cooperative Epigenetic Modulation by Cancer Amplicon Genes

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