CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma

Takuro Kameda; Kotaro Shide; Ayako Kamiunten; Yasunori Kogure; Daisuke Morishita; Junji Koya; Yuki Tahira; Keiichi Akizuki; Takako Yokomizo-Nakano; Sho Kubota; Kosuke Marutsuka; Masaaki Sekine; Tomonori Hidaka; Yoko Kubuki; Yuichi Kitai; Tadashi Matsuda; Akinori Yoda; Takayuki Ohshima; Midori Sugiyama; Goro Sashida; Keisuke Kataoka; Seishi Ogawa; Kazuya Shimoda

doi:10.1038/s42003-022-04284-x

CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma

Takuro Kameda, Kotaro Shide, Ayako Kamiunten, Yasunori Kogure, Daisuke Morishita, Junji Koya, Yuki Tahira, Keiichi Akizuki, Takako Yokomizo-Nakano, Sho Kubota, Kosuke Marutsuka, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Yuichi Kitai, Tadashi Matsuda, Akinori Yoda, Takayuki Ohshima, Midori Sugiyama, Goro SashidaKeisuke Kataoka, Seishi Ogawa, Kazuya Shimoda

Department of Internal Medicine (Hematology)

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

Abstract

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4⁺ T cell-specific CARD11(E626K) and/or CD4⁺ T cell-specific HBZ, namely CARD11(E626K)^CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)^CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)^CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4⁺ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

Original language	English
Article number	1309
Journal	Communications biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-04284-x
Publication status	Published - 2022 Dec

ASJC Scopus subject areas

Medicine (miscellaneous)
Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42003-022-04284-x

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Kameda, T., Shide, K., Kamiunten, A., Kogure, Y., Morishita, D., Koya, J., Tahira, Y., Akizuki, K., Yokomizo-Nakano, T., Kubota, S., Marutsuka, K., Sekine, M., Hidaka, T., Kubuki, Y., Kitai, Y., Matsuda, T., Yoda, A., Ohshima, T., Sugiyama, M., ... Shimoda, K. (2022). CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma. Communications biology, 5(1), [1309]. https://doi.org/10.1038/s42003-022-04284-x

Kameda, T, Shide, K, Kamiunten, A, Kogure, Y, Morishita, D, Koya, J, Tahira, Y, Akizuki, K, Yokomizo-Nakano, T, Kubota, S, Marutsuka, K, Sekine, M, Hidaka, T, Kubuki, Y, Kitai, Y, Matsuda, T, Yoda, A, Ohshima, T, Sugiyama, M, Sashida, G, Kataoka, K, Ogawa, S & Shimoda, K 2022, 'CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma', Communications biology, vol. 5, no. 1, 1309. https://doi.org/10.1038/s42003-022-04284-x

@article{01e6ccbc79a8449b9f4c0885e94f9df3,

title = "CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma",

abstract = "Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes{\textquoteright} pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.",

author = "Takuro Kameda and Kotaro Shide and Ayako Kamiunten and Yasunori Kogure and Daisuke Morishita and Junji Koya and Yuki Tahira and Keiichi Akizuki and Takako Yokomizo-Nakano and Sho Kubota and Kosuke Marutsuka and Masaaki Sekine and Tomonori Hidaka and Yoko Kubuki and Yuichi Kitai and Tadashi Matsuda and Akinori Yoda and Takayuki Ohshima and Midori Sugiyama and Goro Sashida and Keisuke Kataoka and Seishi Ogawa and Kazuya Shimoda",

note = "Funding Information: The authors would like to thank M. Takeyama and Y. Nakamura (Axcelead Drug Discovery Partners, Inc.) for their technical assistance with the generation of CARD11(E626K)stopFL mice, and S. Saito, M. Matsushita, and T. Shinmori for their technical assistance with the experiments. This work was supported by Grants-in-Aid for Scientific Research (C) (17K09931, 20K08715) (T.K.) from the Japan Society for the Promotion of Science, by Research Grants (H28) (T.K.) from the Shinnihon Foundation of Advanced Medical Treatment Research, by Research Grants (R1) (T.K.) from The Japanese Society of Hematology, and by Research Grants (K. Shimoda; 20ck0106538h0001: S.O; 20ck0106409h0003) from the Japan Agency for Medical Research and Development (AMED). This study was supported by the Frontier Science Research Center, University of Miyazaki. Cell sorting experiments were supported by Y. Kawagoe. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-04284-x",

language = "English",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma

AU - Kameda, Takuro

AU - Shide, Kotaro

AU - Kamiunten, Ayako

AU - Kogure, Yasunori

AU - Morishita, Daisuke

AU - Koya, Junji

AU - Tahira, Yuki

AU - Akizuki, Keiichi

AU - Yokomizo-Nakano, Takako

AU - Kubota, Sho

AU - Marutsuka, Kosuke

AU - Sekine, Masaaki

AU - Hidaka, Tomonori

AU - Kubuki, Yoko

AU - Kitai, Yuichi

AU - Matsuda, Tadashi

AU - Yoda, Akinori

AU - Ohshima, Takayuki

AU - Sugiyama, Midori

AU - Sashida, Goro

AU - Kataoka, Keisuke

AU - Ogawa, Seishi

AU - Shimoda, Kazuya

N1 - Funding Information: The authors would like to thank M. Takeyama and Y. Nakamura (Axcelead Drug Discovery Partners, Inc.) for their technical assistance with the generation of CARD11(E626K)stopFL mice, and S. Saito, M. Matsushita, and T. Shinmori for their technical assistance with the experiments. This work was supported by Grants-in-Aid for Scientific Research (C) (17K09931, 20K08715) (T.K.) from the Japan Society for the Promotion of Science, by Research Grants (H28) (T.K.) from the Shinnihon Foundation of Advanced Medical Treatment Research, by Research Grants (R1) (T.K.) from The Japanese Society of Hematology, and by Research Grants (K. Shimoda; 20ck0106538h0001: S.O; 20ck0106409h0003) from the Japan Agency for Medical Research and Development (AMED). This study was supported by the Frontier Science Research Center, University of Miyazaki. Cell sorting experiments were supported by Y. Kawagoe. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

AB - Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

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ER -

CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma

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