Details of the Researcher

PHOTO

Mikiko Suzuki
Section
Graduate School of Medicine
Job title
Associate Professor
Degree

  • 博士（医学）（筑波大学）

  • 修士（医科学）（筑波大学）

Research Areas 2

  • Life sciences / Medical biochemistry /

  • Life sciences / Tumor biology /

Awards 2

  1. 奨励賞

    2016/09　日本生化学会

  2. 東北大学医学部奨学賞・銀賞

    2010/01/15　東北大学

Papers 48

  1. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice Peer-reviewed

    Shimizu R, Hirano I, Hasegawa A, Suzuki M, Otsuki A, Taguchi K, Katsuoka F, Uruno A, Suzuki N, Yumoto A, Okada R, Shrakawa M, Shiba D, Takahashi S, Suzuki T, Yamamoto M

    Commun Biol　6　2023/08

    DOI： 10.1038/s42003-022-03316-w 　

  2. Selective Elimination of NRF2-Activated Cells by Competition with Neighboring Cells in the Esophageal Epithelium. International-journal

    Wataru Hirose, Makoto Horiuchi, Donghan Li, Ikuko N Motoike, Lin Zhang, Hafumi Nishi, Yusuke Taniyama, Takashi Kamei, Mikiko Suzuki, Kengo Kinoshita, Fumiki Katsuoka, Keiko Taguchi, Masayuki Yamamoto

    Cellular and molecular gastroenterology and hepatology　15　(1)　153-178　2022/09/14

    DOI： 10.1016/j.jcmgh.2022.09.004 　

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    BACKGROUND & AIMS: NF-E2-related factor 2 (NRF2) is a transcription factor that regulates cytoprotective gene expression in response to oxidative and electrophilic stresses. NRF2 activity is mainly controlled by Kelch-like ECH-associated protein 1 (KEAP1). Constitutive NRF2 activation by NRF2 mutations or KEAP1 dysfunction results in a poor prognosis for esophageal squamous cell carcinoma (ESCC) through the activation of cytoprotective functions. However, the detailed contributions of NRF2 to ESCC initiation or promotion have not been clarified. Here, we investigated the fate of NRF2-activated cells in the esophageal epithelium. METHODS: We generated tamoxifen-inducible, squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which NRF2 was inducibly activated in a subset of cells at the adult stage. Histological, quantitative reverse-transcription polymerase chain reaction (qRT‒PCR), single-cell RNA-sequencing (RNA-seq) and carcinogen experiments were conducted to analyze the Keap1-cKO esophagus. RESULTS: KEAP1-deleted/NRF2-activated cells and cells with normal NRF2 expression (KEAP1-normal cells) coexisted in the Keap1-cKO esophageal epithelium in approximately equal numbers, and NRF2-activated cells formed dysplastic lesions. NRF2-activated cells exhibited weaker attachment to the basement membrane and gradually disappeared from the epithelium. In contrast, neighboring KEAP1-normal cells exhibited accelerated proliferation and started dominating the epithelium but accumulated DNA damage that triggered carcinogenesis upon carcinogen exposure. CONCLUSIONS: Constitutive NRF2 activation promotes the selective elimination of epithelial cells via cell competition, but this competition induces DNA damage in neighboring KEAP1-normal cells, which predisposes them to chemical-induced ESCC.

  3. The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. International-journal

    Ayumi Kuga, Kouhei Tsuchida, Harit Panda, Makoto Horiuchi, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Mikiko Suzuki, Masayuki Yamamoto

    Molecular and cellular biology　42　(7)　e0056321　2022/07/21

    DOI： 10.1128/mcb.00563-21 　

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    Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP. The homozygous (Nrf2SA/SA) mice grew normally, with Nrf2 levels comparable to those of wild-type (WT) mice under unstressed conditions. However, when Keap1 activity was suppressed, high levels of Nrf2 accumulated in Nrf2SA/SA macrophages compared with that in WT macrophages. We crossed Nrf2SA/SA mice with mice in which Keap1 was knocked down to two different levels. We found that the Nrf2SA/SA mutation induced higher Nrf2 activity when the Keap1 level was strongly reduced, and these mice showed severe growth retardation. However, activation and growth retardation were not evident when Keap1 was moderately suppressed. These increases in Nrf2 activity induced by the Nrf2SA mutation caused severe hyperplasia and hyperkeratosis in the esophageal epithelium but did not cause abnormalities in the other tissues/organs examined. These results indicate that the β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway to regulate Nrf2 activity, which is apparent when the Keap1-mediated pathway is profoundly suppressed.

  4. Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity. International-journal

    Harit Panda, Mikiko Suzuki, Mitsuru Naito, Ritsumi Saito, Huaichun Wen, Liam Baird, Akira Uruno, Kanjiro Miyata, Masayuki Yamamoto

    Free radical biology & medicine　187　92-104　2022/07

    DOI： 10.1016/j.freeradbiomed.2022.05.017 　

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    The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

  5. Multifaceted Roles of the KEAP1-NRF2 System in Cancer and Inflammatory Disease Milieu. International-journal

    Harit Panda, Huaichun Wen, Mikiko Suzuki, Masayuki Yamamoto

    Antioxidants (Basel, Switzerland)　11　(3)　2022/03/11

    DOI： 10.3390/antiox11030538 　

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    In a multicellular environment, many different types of cells interact with each other. The KEAP1-NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1-NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1-NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1-NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1-NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.

  6. Nrf2 plays a critical role in the metabolic response during and after spaceflight

    Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W. Kensler, Dai Shiba, Masayuki Yamamoto

    Communications Biology　4　(1)　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-021-02904-6 　

    eISSN： 2399-3642

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    <title>Abstract</title>Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by <italic>Nrf2</italic> knockout. We conducted metabolome analyses of plasma from wild-type and <italic>Nrf2</italic> knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in <italic>Nrf2</italic> knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of <italic>Nrf2</italic> knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

  7. Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel

    Norio Suzuki, Yuma Iwamura, Taku Nakai, Koichiro Kato, Akihito Otsuki, Akira Uruno, Daisuke Saigusa, Keiko Taguchi, Mikiko Suzuki, Ritsuko Shimizu, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Kidney International　2021/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.kint.2021.09.031 　

    ISSN： 0085-2538

  8. NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition. International-journal

    Tsuyoshi Waku, Toru Hagiwara, Natsuko Tamura, Yuri Atsumi, Yasuomi Urano, Mikiko Suzuki, Takuya Iwami, Katsuya Sato, Masayuki Yamamoto, Noriko Noguchi, Akira Kobayashi

    iScience　24　(10)　103180-103180　2021/10/22

    DOI： 10.1016/j.isci.2021.103180 　

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    Lipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of the GGPS1 gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.

  9. 転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

    堀内 真, 谷山 裕亮, 田口 恵子, 鈴木 未来子, 山本 雅之, 亀井 尚

    日本外科学会定期学術集会抄録集　121回　PS-5　2021/04

    Publisher: (一社)日本外科学会

  10. Cellular Nrf2 Levels Determine Cell Fate during Chemical Carcinogenesis in Esophageal Epithelium. International-journal

    Makoto Horiuchi, Keiko Taguchi, Wataru Hirose, Kouhei Tsuchida, Mikiko Suzuki, Yusuke Taniyama, Takashi Kamei, Masayuki Yamamoto

    Molecular and cellular biology　41　(2)　2021/01/25

    DOI： 10.1128/MCB.00536-20 　

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    Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.

  11. 転写因子Nrf2の活性化が引き起こす食道異形成と発がんにおける細胞選択性

    堀内 真, 田口 恵子, 鈴木 未来子, 谷山 裕亮, 山本 雅之, 亀井 尚

    日本食道学会学術集会プログラム・抄録集　74回　110-110　2020/12

    Publisher: (NPO)日本食道学会

  12. Author Correction: Nrf2 contributes to the weight gain of mice during space travel. International-journal

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology　3　(1)　566-566　2020/10/07

    DOI： 10.1038/s42003-020-01292-7 　

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  13. Nrf2 contributes to the weight gain of mice during space travel. International-journal Peer-reviewed

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology　3　(1)　496-496　2020/09/08

    DOI： 10.1038/s42003-020-01227-2 　

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    Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

  14. Microenvironmental Activation of Nrf2 Restricts the Progression of Nrf2-Activated Malignant Tumors. International-journal Peer-reviewed

    Makiko Hayashi, Ayumi Kuga, Mikiko Suzuki, Harit Panda, Hiroshi Kitamura, Hozumi Motohashi, Masayuki Yamamoto

    Cancer research　80　(16)　3331-3344　2020/08/15

    DOI： 10.1158/0008-5472.CAN-19-2888 　

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    The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects. SIGNIFICANCE: This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.

  15. EVI1 and GATA2 misexpression induced by inv(3)(q21q26) contribute to megakaryocyte-lineage skewing and leukemogenesis. International-journal Peer-reviewed

    Ayaka Yamaoka, Mikiko Suzuki, Saori Katayama, Daiki Orihara, James Douglas Engel, Masayuki Yamamoto

    Blood advances　4　(8)　1722-1736　2020/04/28

    DOI： 10.1182/bloodadvances.2019000978 　

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    Chromosomal rearrangements between 3q21 and 3q26 elicit high-risk acute myeloid leukemia (AML), which is often associated with elevated platelet and megakaryocyte (Mk) numbers. The 3q rearrangements reposition a GATA2 enhancer near the EVI1 (or MECOM) locus, which results in both EVI1 overexpression and GATA2 haploinsufficiency. However, the mechanisms explaining how the misexpression of these 2 genes individually contribute to leukemogenesis are unknown. To clarify the characteristics of differentiation defects caused by EVI1 and GATA2 misexpression and to identify the cellular origin of leukemic cells, we generated a system to monitor both inv(3) allele-driven EVI1 and Gata2 expression in 3q-rearranged AML model mice. A cell population in which both EVI1 and Gata2 were highly induced appeared in the bone marrows before the onset of frank leukemia. This population had acquired serial colony-forming potential. Because hematopoietic stem/progenitor cells (HSPCs) and Mks were enriched in this peculiar population, we analyzed the independent EVI1 and GATA2 contributions to HSPC and Mk. We found that inv(3)-driven EVI1 promotes accumulation of Mk-biased and myeloid-biased progenitors, Mks, and platelets, and that Gata2 heterozygous deletion enhanced Mk-lineage skewing of EVI1-expressing progenitors. Notably, inv(3)-directed EVI1 expression and Gata2 haploinsufficient expression cooperatively provoke a leukemia characterized by abundant Mks and platelets. These hematological features of the mouse model phenocopy those observed in human 3q AML. On the basis of these results, we conclude that inv(3)-driven EVI1 expression in HSPCs and Mks collaborates with Gata2 haploinsufficiency to provoke Mk-lineage skewing and leukemogenesis with excessive platelets, thus mimicking an important feature of human AML.

  16. Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites. International-journal Peer-reviewed

    Daisuke Saigusa, Ikuko N Motoike, Sakae Saito, Michael Zorzi, Yuichi Aoki, Hiroshi Kitamura, Mikiko Suzuki, Fumiki Katsuoka, Hirofumi Ishii, Kengo Kinoshita, Hozumi Motohashi, Masayuki Yamamoto

    Cancer science　111　(2)　667-678　2020/02

    DOI： 10.1111/cas.14278 　

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    Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.

  17. Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements. International-journal Peer-reviewed

    Mikiko Suzuki, Saori Katayama, Masayuki Yamamoto

    IUBMB life　72　(1)　159-169　2020/01

    DOI： 10.1002/iub.2191 　

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    Chromosomal inversion and translocation between 3q21 and 3q26 [inv (3)(q21.3q26.2) and t(3;3)(q21.3;q26.2), respectively] give rise to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), which have poor prognoses. The chromosomal rearrangements reposition a GATA2 distal hematopoietic enhancer from the original 3q21 locus to the EVI1 (also known as MECOM) locus on 3q26. Therefore, the GATA2 enhancer from one of two GATA2 alleles drives EVI1 gene expression in hematopoietic stem and progenitor cells, which promotes the accumulation of abnormal progenitors and induces leukemogenesis. On the other hand, one allele of the GATA2 gene loses its enhancer, which results in reduced GATA2 expression. The GATA2 gene encodes a transcription factor critical for the generation and maintenance of hematopoietic stem and progenitor cells. GATA2 haploinsufficiency has been known to cause immunodeficiency and myeloid leukemia. Notably, reduced GATA2 expression suppresses the differentiation but promotes the proliferation of EVI1-expressing leukemic cells, which accelerates EVI1-driven leukemogenesis. A series of studies have shown that the GATA2 enhancer repositioning caused by the chromosomal rearrangements between 3q21 and 3q26 provokes misexpression of both the EVI1 and GATA2 genes and that these two effects coordinately elicit high-risk leukemia.

  18. Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model. Peer-reviewed

    Panda H, Keleku-Lukwete N, Kuga A, Fuke N, Suganuma H, Suzuki M, Yamamoto M

    Experimental hematology　2019/08

    DOI： 10.1016/j.exphem.2019.08.001 　

    ISSN： 0301-472X

  19. Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. International-journal Peer-reviewed

    Keleku-Lukwete N, Suzuki M, Panda H, Otsuki A, Katsuoka F, Saito R, Saigusa D, Uruno A, Yamamoto M

    Blood advances　3　(8)　1285-1297　2019/04

    DOI： 10.1182/bloodadvances.2018017574 　

    ISSN： 2473-9529

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    Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower Tnfα and Il1β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.

  20. An Overview of the Advantages of KEAP1-NRF2 System Activation During Inflammatory Disease Treatment. Peer-reviewed

    Keleku-Lukwete N, Suzuki M, Yamamoto M

    Antioxidants & redox signaling　29　(17)　1746-1755　2018/12

    DOI： 10.1089/ars.2017.7358 　

    ISSN： 1523-0864

  21. 3番染色体転座・逆位を伴う白血病におけるGATA2遺伝子発現減少の貢献

    鈴木 未来子, 山岡 彩香, 片山 紗乙莉, 山本 雅之

    生命科学系学会合同年次大会　2017年度　[2P-0884]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  22. GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis Peer-reviewed

    Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto

    BLOOD　130　(7)　908-919　2017/08

    DOI： 10.1182/blood-2016-12-756767 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  23. Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis Peer-reviewed

    Lei Yu, Jun Takai, Akihito Otsuki, Fumiki Katsuoka, Mikiko Suzuki, Saori Katayama, Masahiro Nezu, James Douglas Engel, Takashi Moriguchi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　37　(8)　2017/04

    DOI： 10.1128/MCB.00592-16 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  24. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation Peer-reviewed

    Kouhei Tsuchida, Tadayuki Tsujita, Makiko Hayashi, Asaka Ojima, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Haruhisa Kikuchi, Yoshiteru Oshima, Mikiko Suzuki, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　103　236-247　2017/02

    DOI： 10.1016/j.freeradbiomed.2016.12.041 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  25. Chromosomal rearrangements between 3q21 and 3q26 induce leukemogenesis by misdirecting both EVI1 and GATA2 genes. Peer-reviewed

    Suzuki M

    [Rinsho ketsueki] The Japanese journal of clinical hematology　58　(7)　806-812　2017

    DOI： 10.11406/rinketsu.58.806 　

    ISSN： 0485-1439

  26. Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection Peer-reviewed

    Akihito Otsuki, Mikiko Suzuki, Fumiki Katsuoka, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Ritsuko Shimizu, Masayuki Yamamoto

    FREE RADICAL BIOLOGY AND MEDICINE　91　45-57　2016/02

    DOI： 10.1016/j.freeradbiomed.2015.12.005 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  27. Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation Peer-reviewed

    Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Doug Engel, Masue Imaizumi, Masayuki Yamamoto

    BLOOD　126　(23)　2015/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  28. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation Peer-reviewed

    Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　112　(39)　12169-12174　2015/09

    DOI： 10.1073/pnas.1509158112 　

    ISSN： 0027-8424

  29. The Human GATA1 Gene Retains a 5 ' Insulator That Maintains Chromosomal Architecture and GATA1 Expression Levels in Splenic Erythroblasts Peer-reviewed

    Takashi Moriguchi, Lei Yu, Jun Takai, Makiko Hayashi, Hironori Satoh, Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　35　(10)　1825-1837　2015/05

    DOI： 10.1128/MCB.00011-15 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  30. Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression Peer-reviewed

    Takashi Moriguchi, Mikiko Suzuki, Lei Yu, Jun Takai, Kinuko Ohneda, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　35　(5)　805-815　2015/03

    DOI： 10.1128/MCB.01011-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  31. EVI1陽性白血病においてEVI1発現量が白血病細胞の分化形態を規定する

    鈴木 未来子, 片山 紗乙莉, 山嵜 博未, Engel James Douglas, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　87回　[3P-420]　2014/10

    Publisher: (公社)日本生化学会

  32. Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the beta-Globinopathies

    Mikiko Suzuki, Masayuki Yamamoto, James Douglas Engel

    MOLECULAR AND CELLULAR BIOLOGY　34　(19)　3560-3569　2014/10

    DOI： 10.1128/MCB.00714-14 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  33. Mouse Spermatogenic Stem Cells Continually Interconvert between Equipotent Singly Isolated and Syncytial States Peer-reviewed

    Kenshiro Hara, Toshinori Nakagawa, Hideki Enomoto, Mikiko Suzuki, Masayuki Yamamoto, Benjamin D. Simons, Shosei Yoshida

    CELL STEM CELL　14　(5)　658-672　2014/05

    DOI： 10.1016/j.stem.2014.01.019 　

    ISSN： 1934-5909

    eISSN： 1875-9777

  34. A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression Peer-reviewed

    Hiromi Yamazaki, Mikiko Suzuki, Akihito Otsuki, Ritsuko Shimizu, Emery H. Bresnick, James Douglas Engel, Masayuki Yamamoto

    CANCER CELL　25　(4)　415-427　2014/04

    DOI： 10.1016/j.ccr.2014.02.008 　

    ISSN： 1535-6108

    eISSN： 1878-3686

  35. GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation Peer-reviewed

    Mikiko Suzuki, Maki Kobayashi-Osaki, Shuichi Tsutsumi, Xiaoqing Pan, Shin'ya Ohmori, Jun Takai, Takashi Moriguchi, Osamu Ohneda, Kinuko Ohneda, Ritsuko Shimizu, Yasuharu Kanki, Tatsuhiko Kodama, Hiroyuki Aburatani, Masayuki Yamamoto

    GENES TO CELLS　18　(11)　921-933　2013/11

    DOI： 10.1111/gtc.12086 　

    ISSN： 1356-9597

    eISSN： 1365-2443

  36. The Gata1 5 ' region harbors distinct cis-regulatory modules that direct gene activation in erythroid cells and gene inactivation in HSCs Peer-reviewed

    Jun Takai, Takashi Moriguchi, Mikiko Suzuki, Lei Yu, Kinuko Ohneda, Masayuki Yamamoto

    BLOOD　122　(20)　3450-3460　2013/11

    DOI： 10.1182/blood-2013-01-476911 　

    ISSN： 0006-4971

    eISSN： 1528-0020

  37. Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain Peer-reviewed

    Harumi Y. Mukai, Mikiko Suzuki, Masumi Nagano, Shin'ya Ohmori, Akihito Otsuki, Kouhei Tsuchida, Takashi Moriguchi, Kinuko Ohneda, Ritsuko Shimizu, Osamu Ohneda, Masayuki Yamamoto

    Genes to Cells　18　(10)　886-898　2013/10

    DOI： 10.1111/gtc.12084 　

    ISSN： 1356-9597 1365-2443

  38. Disruption of the Hbs1L-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model Peer-reviewed

    Mikiko Suzuki, Hiromi Yamazaki, Harumi Y. Mukai, Hozumi Motohashi, Lihong Shi, Osamu Tanabe, James Douglas Engel, Masayuki Yamamoto

    Molecular and Cellular Biology　33　(8)　1687-1695　2013/04

    DOI： 10.1128/MCB.01617-12 　

    ISSN： 0270-7306 1098-5549

  39. Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome Peer-reviewed

    Tsutomu Toki, Rika Kanezaki, Eri Kobayashi, Hiroshi Kaneko, Mikiko Suzuki, RuNan Wang, Kiminori Terui, Hirokazu Kanegane, Miho Maeda, Mikiya Endo, Tatsuki Mizuochi, Souichi Adachi, Yasuhide Hayashi, Masayuki Yamamoto, Ritsuko Shimizu, Etsuro Ito

    Blood　121　(16)　3181-3184　2013

    Publisher: American Society of Hematology

    DOI： 10.1182/blood-2012-01-405746 　

    ISSN： 1528-0020 0006-4971

  40. Regulation of GATA Factor Expression Is Distinct between Erythroid and Mast Cell Lineages Peer-reviewed

    Shin'ya Ohmori, Jun Takai, Yasushi Ishijima, Mikiko Suzuki, Takashi Moriguchi, Sjaak Philipsen, Masayuki Yamamoto, Kinuko Ohneda

    MOLECULAR AND CELLULAR BIOLOGY　32　(23)　4742-4755　2012/12

    DOI： 10.1128/MCB.00718-12 　

    ISSN： 0270-7306

  41. Transcriptional regulation by GATA1 and GATA2 during erythropoiesis

    Mikiko Suzuki, Ritsuko Shimizu, Masayuki Yamamoto

    INTERNATIONAL JOURNAL OF HEMATOLOGY　93　(2)　150-155　2011/02

    DOI： 10.1007/s12185-011-0770-6 　

    ISSN： 0925-5710

  42. Genetic Analysis of Hierarchical Regulation for Gata1 and NF-E2 p45 Gene Expression in Megakaryopoiesis Peer-reviewed

    Mariko Takayama, Rie Fujita, Mikiko Suzuki, Ryuhei Okuyama, Setsuya Aiba, Hozumi Motohashi, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY　30　(11)　2668-2680　2010/06

    DOI： 10.1128/MCB.01304-09 　

    ISSN： 0270-7306

  43. Differential contribution of the Gata1 gene hematopoietic enhancer to erythroid differentiation. International-journal Peer-reviewed

    Suzuki Mikiko, Moriguchi Takashi, Ohneda Kinuko, Yamamoto Masayuki

    Mol Cell Biol　29　(5)　1163-1175　2009/03

    DOI： 10.1128/MCB.01572-08 　

    More details Close

    GATA1 is a key regulator of erythroid cell differentiation. To examine how Gata1 gene expression is regulated in a stage-specific manner, transgenic mouse lines expressing green fluorescent protein (GFP) reporter from the Gata1 locus in a bacterial artificial chromosome (G1BAC-GFP) were prepared. We found that the GFP reporter expression faithfully recapitulated Gata1 gene expression. Using GFP fluorescence in combination with hematopoietic surface markers, we established a purification protocol for two erythroid progenitor fractions, referred to as burst-forming units-erythroid cell-related erythroid progenitor (BREP) and CFU-erythroid cell-related erythroid progenitor (CREP) fractions. We examined the functions of the Gata1 gene hematopoietic enhancer (G1HE) and the highly conserved GATA box in the enhancer core. Both deletion of the G1HE and substitution mutation of the GATA box caused almost complete loss of GFP expression in the BREP fraction, but the CREP stage expression was suppressed only partially, indicating the critical contribution of the GATA box to the BREP stage expression of Gata1. Consistently, targeted deletion of G1HE from the chromosomal Gata1 locus provoked suppressed expression of the Gata1 gene in the BREP fraction, which led to aberrant accumulation of BREP stage hematopoietic progenitor cells. These results demonstrate the physiological significance of the dynamic regulation of Gata1 gene expression in a differentiation stage-specific manner.

  44. Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropolesis Peer-reviewed

    Laura Gutierrez, Saho Tsukamoto, Mikiko Suzuki, Harumi Yamamoto-Mukai, Masayuki Yamamoto, Sjaak Philipsen, Kinuko Ohneda

    BLOOD　111　(8)　4375-4385　2008/04

    DOI： 10.1182/blood-2007-09-115121 　

    ISSN： 0006-4971

  45. GATA-4 incompletely substitutes for GATA-1 in promoting both primitive and definitive erythropoiesis in vivo Peer-reviewed

    Sakie Hosoya-Ohmura, Naomi Mochizuki, Mikiko Suzuki, Osamu Ohneda, Kinuko Ohneda, Masayuki Yamamoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(43)　32820-32830　2006/10

    DOI： 10.1074/jbc.M605735200 　

    ISSN： 0021-9258

  46. Real-time monitoring of stress erythropoiesis in vivo using Gata1 and beta-globin LCR luciferase transgenic mice Peer-reviewed

    Mikiko Suzuki, Kinuko Ohneda, Sakie Hosoya-Ohmura, Saho Tsukamoto, Osamu Ohneda, Sjaak Philipsen, Masayuki Yamamoto

    BLOOD　108　(2)　726-733　2006/07

    DOI： 10.1182/blood-2005-10-4064 　

    ISSN： 0006-4971

  47. Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells Peer-reviewed

    M Nakano, K Ohneda, H Yamamoto-Mukai, R Shimizu, O Ohneda, S Ohmura, M Suzuki, S Tsukamoto, T Yanagawa, H Yoshida, Y Takakuwa, M Yamamoto

    GENES TO CELLS　10　(1)　47-62　2005/01

    DOI： 10.1111/j.1365-2443.2005.00814.x 　

    ISSN： 1356-9597

  48. Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness Peer-reviewed

    T Kudo, S Kure, K Ikeda, AP Xia, Y Katori, M Suzuki, K Kojima, A Ichinohe, Y Suzuki, Y Aoki, T Kobayashi, Y Matsubara

    HUMAN MOLECULAR GENETICS　12　(9)　995-1004　2003/05

    DOI： 10.1093/hmg/ddg116 　

    ISSN： 0964-6906

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Misc. 15

  1. Identification and analysis of a distal Gata2 enhancer that is required for increasing Gata2 gene expression during mast cell and basophil maturation

    大森慎也, 鈴木未来子, 高井淳, 森口尚, 森哲哉, 大根田絹子

    日本分子生物学会年会プログラム・要旨集(Web)　46th　2023

  2. GATA2ハプロ不全はEVI1誘導性白血病の発症を促進する

    片山 紗乙莉, 鈴木 未来子, 笹原 洋二, 呉 繁夫, 山本 雅之

    日本小児血液・がん学会雑誌　56　(2)　159-162　2019/09

    Publisher: (一社)日本小児血液・がん学会

    ISSN： 2187-011X

    eISSN： 2189-5384

  3. Diseases associated with GATA2 gene enhancer abnormalities

    Mikiko Suzuki

    Seikagaku　89　(3)　391-399　2017

    Publisher: Japanese Biochemical Society

    DOI： 10.14952/SEIKAGAKU.2017.890391 　

    ISSN： 2189-0544 0037-1017

  4. Specific Deletion of Keap1 in Endothelial Cells or/and Macrophages of SCD Mice Induces Nrf2 to Protect Tissues Against Oxidative Insults

    Nadine Keleku-Lukwete, Panda Harit, Eriko Naganuma, Mikiko Suzuki, Masayuki Yamamoto

    BLOOD　128　(22)　2016/12

    ISSN： 0006-4971

    eISSN： 1528-0020

  5. GATA2遺伝子ヘテロ欠失は3番染色体逆位を伴う白血病の発症を促進する

    片山 紗乙莉, 鈴木 未来子, 呉 繁夫, 山本 雅之

    日本生化学会大会プログラム・講演要旨集　89回　[2T07-01(2P　2016/09

    Publisher: (公社)日本生化学会

  6. Overview of redox regulation by Keap1–Nrf2 system in toxicology and cancer

    Mikiko Suzuki, Akihito Otsuki, Nadine Keleku-Lukwete, Masayuki Yamamoto

    Current Opinion in Toxicology　1　29-36　2016

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.cotox.2016.10.001 　

    ISSN： 2468-2020

  7. 生体防御因子Nrf2の遺伝的および薬剤誘導的活性化は多発性硬化症の症状を改善する

    林真貴子, 森口尚, 森口尚, 鈴木未来子, 鈴木未来子, 小林枝里, 山本雅之, 山本雅之

    日本生化学会大会(Web)　89th　ROMBUNNO.2T17‐06(2P‐362) (WEB ONLY)-362)]　2016

    Publisher: (公社)日本生化学会

  8. Generation of Nrf2 point mutant mice by CRISPR/Cas9 system

    Masanobu Morita, Takafumi Suzuki, Hiromi Suda, Akihito Otsuki, Mikiko Suzuki, Ritsuko Shimizu, Masayuki Yamamoto

    TRANSGENIC RESEARCH　23　(5)　874-874　2014/10

    ISSN： 0962-8819

    eISSN： 1573-9368

  9. BACトランスジェニックマウスを用いた血球分化マスター転写因子GATA1の遺伝子発現制御機構の解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    生化学　85　(8)　720-720　2013/08

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  10. 転写因子GATA2によるG1サイクリン遺伝子発現の制御

    峯岸直子, 鈴木教郎, 鈴木未来子, 張替秀郎, 山本雅之

    生化学　83回・33回　2T8-4　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  11. Gata1遺伝子発現制御機構のBACトランスジェニックマウスを用いた解析

    高井 淳, 森口 尚, 鈴木 未来子, 大根田 絹子, 山本 雅之

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0548　2010/12

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  12. BACトランスジェニックマウスを用いたGata1遺伝子発現制御機構の解析

    森口 尚, 鈴木 未来子, 高井 淳, 山本 雅之

    生化学　81　(6)　536-536　2009/06

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  13. Gata1遺伝子発現制御領域の血球分化段階特異的な機能的貢献

    森口尚, 鈴木未来子, 高井淳, 大根田絹子, 山本雅之

    生化学　2008

    ISSN： 0037-1017

  14. G1HE-core contributes to the stage-specific expression of the Gata1 gene during erythroid development

    Mikiko Suzuki, Kinuko Ohneda, Masayuki Yamamoto

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　180-180　2007/03

    DOI： 10.1016/j.bcmd.2006.10.135 　

    ISSN： 1079-9796

  15. Regulation of mouse Gatal gene expression in erythroid progenitors

    Masayuki Yamamoto, Mikiko Suzuki, Norio Suzuki, Ritsuko Shimizu

    BLOOD CELLS MOLECULES AND DISEASES　38　(2)　188-188　2007/03

    DOI： 10.1016/j.bcmd.2006.10.153 　

    ISSN： 1079-9796

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Presentations 20

  1. GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis International-presentation Invited

    SUZUKI MikikoMikiko Suzuki, Saori Katayama, Ayaka Yamaoka, James Douglas Engel, Masayuki Yamamoto

    IUBMB Focused Meeting on GATA Transcription Factors　2018/05/31

  2. エンハンサーハイジャッキングによる白血病発症機構 Invited

    鈴木未来子

    小児科イブニングカンファレンス　2017/04/11

  3. Chromosomal rearrangements between 3q21 and 3q26 induce leukemogenesis by misdirecting both EVI1 and GATA2 genes International-presentation Invited

    SUZUKI Mikiko

    2016/10/13

  4. エンハンサーの破綻が引き起こす血液疾患の解析 Invited

    鈴木未来子

    第89回日本生化学会大会　2016/09/26

  5. 染色体転座を伴う白血病モデルマウスの開発とEVI1陽性白血病の解析 Invited

    鈴木未来子

    第386回東北医学会例会シンポジウム　2015/11/17

  6. 染色体転座による原がん遺伝子EVI1誘導機構の解析 Invited

    鈴木未来子

    第8回Symphony　2015/09/26

  7. 染色体転座に起因する白血病誘導エンハンサーの解析 Invited

    鈴木未来子

    第26回がん・エピゲノム研究会　2015/07/29

  8. A novel mouse model harboring human inv(3)(q21;q26) allele reveals mechanisms underlying EVI1-expressing leukemia International-presentation Invited

    SUZUKI Mikiko

    Functional Genomics and Experimental Medicine　2015/02/03

  9. 染色体転座・逆位におけるEVI1遺伝子活性化および白血病発症機構の解析 Invited

    鈴木未来子, 山㟢博未, 大槻晃史, 清水律子, Emery H. Bresnick, James Douglas Engel, 山本雅之

    第10回血液学若手研究者勉強会（麒麟塾）　2014/07/12

  10. 染色体転座・逆位によるEVI1発現白血病の新規マウスモデル樹立とEVI1遺伝子発現制御解析

    鈴木未来子, 山㟢博未, 大槻晃史, 清水律子, Emery H. Bresnick, James Douglas Engel, 山本雅之

    平成25年度「個体レベルでのがん研究支援活動」ワークショップ 個体レベルからみた炎症とがん　2014/02/17

  11. GATA2遺伝子エンハンサーがinv(3)(q21;q26)においてEVI1遺伝子を活性化し白血病を誘発する

    鈴木未来子, 山㟢博未, 大槻晃史, 清水律子, Emery H. Bresnick, James Douglas Engel, 山本雅之

    第18回造血器腫瘍研究会　2014/02/07

  12. 白血病逆位モデルマウスを用いたEVI1高発現白血病発症機構の解析

    鈴木未来子, 山㟢博未, 加藤幸一郎, 清水律子, James Douglas Engel, 山本雅之

    第17回造血器腫瘍研究会　2013/02/01

  13. 3q21q26白血病染色体転座・逆位モデルマウスを用いたEVI1遺伝子転写活性化機構の解析

    鈴木未来子, 山㟢博未, 加藤幸一郎, 清水律子, James Douglas Engel, 山本雅之

    若手ワークショップ＠鬼怒川　2013/01/24

  14. 大腸菌人工染色体（BAC）を用いた3q21q26染色体転座・逆位によるEVI1遺伝子高発現白血病モデルマウスの樹立

    鈴木未来子, 山㟢博未, 清水律子, James Douglas Engel, 山本雅之

    日本生化学会 東北支部 第78回例会・シンポジウム　2012/05/26

  15. 大腸菌人工染色体を用いた新しい白血病染色体転座／逆位モデルマウスの構築

    鈴木 未来子, 山嵜 博未, 清水 律子, James Douglas Engel, 山本 雅之

    造血器腫瘍研究会　2012/01/28

  16. Hereditary persistence of fetal hemoglobin is associated with disruption of the HBS1L-MYB locus

    Mikiko Suzuki, Hiromi Yamazaki, Harumi Y. Mukai, Hozumi Motohashi, Lihong Shi, Osamu Tanabe, James Douglas Engel, Masayuki Yamamoto

    日本分子生物学会年会　2011/12/13

  17. HBS1L-MYB遺伝子間領域の変異が巨核球／赤血球運命決定異常と高胎児ヘモグロビン症を誘発する

    鈴木未来子, 向井陽美, 山㟢博未, 本橋ほづみ, James Douglas Engel, 山本雅之

    新学術領域”細胞運命制御”若手の会　2011/09/23

  18. Hereditary persistence of fetal hemoglobin and the HBS1L-MYB locus International-presentation

    Mikiko Suzuki, Harumi Y. Mukai, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

    5th International Symposium on GATA factors　2010/11/17

  19. A mouse model of hereditary persistence of fetal hemoglobin associated with HBS1L-MYB intergenic region International-presentation

    Mikiko Suzuki, Harumi Y. Mukai, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

    The 17th Hemoglobin Switching Meeting　2010/09/02

  20. A Novel Mouse Model of Human Hereditary Persistence of Fetal Hemoglobin (HPFH) Associated with HBS1L-MYB Intergenic Region International-presentation

    Mikiko Suzuki, Harumi Y. Mukai, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto

    JSH International Symposium 2010 in Akita　2010/07/16

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Research Projects 9

  1. EVI1-GATA2バランスによる3q白血病悪性化機構の解析

    鈴木 未来子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2020/04/01 - 2023/03/31

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    前年度、白血病発症前の3番染色体転座モデルマウス（3q21q26-EVI1マウス）の骨髄内に存在するEVI1遺伝子とGATA2遺伝子の発現が両方とも強く誘導されている細胞集団が、白血病細胞と同じ表面マーカー発現（B220陽性c-Kit陽性）を示す細胞を生み出すことを発見した。B220陽性c-Kit陽性細胞は正常骨髄内にはほとんど存在しないことから、この細胞集団が白血病細胞の母体となっていることが考えられた。そこで、今年度はこの細胞の特徴を詳細に解析した。この細胞集団は、Stem cell factor（SCF）、インターロイキン（IL）-3、IL-6、エリスロポエチン含有半固形培地で培養すると、連続的にコロニーを形成した。初回に形成したコロニーはコントロールマウスよりも小さいが、2回目以降に急激に大きなコロニーを形成するようになった。このコロニー増大の後に、B220陽性c-Kit陽性が出現してくることがわかった。培養液中に存在するサイトカインのうち、どれがこの変化に重要であるかを解析するために、コロニー形成細胞におけるサイトカイン受容体の発現を検討したところ、これらの細胞はIL-3受容体を高発現していた。このことから、IL-3シグナルが関与する可能性が示唆された。また今年度は、ゲノム編集により、Gata2遺伝子のエンハンサーを欠失させたマウスを作製した。3番染色体転座白血病では、片アリルのGATA2遺伝子がエンハンサーを失っている。このマウスを利用することにより、3番染色体転座白血病におけるGATA2発現低下をより正確に再現できると期待される。

  2. Conditions for the proto-oncogene EVI1 to induce leukemia

    Suzuki Mikiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2018/06/29 - 2020/03/31

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    By monitoring EVI1 gene expression under the control of inv(3) allele, we found that the EVI1 gene is expressed not only in hematopoietic stem and progenitor cells but also in megakaryocyte lineage, which promotes megakaryocyte-lineage skewing. In addition to EVI1 gene expression, the down-regulation of the GATA2 gene caused by inv(3) promoted the development of leukemia with megakaryocyte hyperplasia, similar to leukemia of human patients. These results indicate that these EVI1 and GATA2 misexpression contribute to the development of leukemia caused by chromosome 3 inversion.

  3. Mechanisms of leukemogenesis by the leukemia-driving enhancer

    Yamamoto Masayuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2015/04/01 - 2019/03/31

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    Chromosomal rearrangement between 3q21 and 3q26 provokes leukemia with poor prognosis. The rearrangement induces misexpression of both misexpression of EVI1 gene and reduction of GATA2 gene expression by translocation of the GATA2 gene enhancer. Here we asked whether GATA2 haploinsufficiency in addition to EVI1 misexpression contributed to leukemogenesis by using a 3q21q26 mouse model that recapitulates the GATA2 enhancer-driven EVI1 misexpression coupled with a Gata2 heterozygous deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemogenesis. While EVI1-misexpressed blast-like cells retained some limited ability to differentiate into myeloid cells, simultaneous loss of one Gata2 allele suppressed the myeloid differentiation and promoted the expansion of these blast-like cells. These results demonstrate that Gata2 heterozygous deletion accelerates EVI1 misexpression leukemia by inducing proliferation and differentiation defect of leukemia cells.

  4. Role of DNA Methyltransferase 1 in the Epigenetic Regulation of Beta-type Globin Genes

    TANABE OSAMU

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2018/03/31

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    Re-induction of embryonic or fetal hemoglobin has therapeutic effects for patients with beta-globin disorders such as beta-thalassemia and sickle cell disease. For the development of therapeutic agents with such effects, the elucidation of the molecular mechanisms for the inactivation of those genes in adult is crucial. In this study, we demonstrated that DNA methyltransferase 1 (DNMT1) is essential for the inactivation of the embryonic beta-type globin gene in adult erythroid cells. Furthermore, we demonstrated that nuclear receptors TR2 and TR4 are essential for the inactivation of the embryonic and fetal beta-type globin genes, as well as for the recruitment of DNMT1 to the promoters of these genes in adult erythroid cells. These results indicate the critical roles of DNMT1 in the inactivation of the embryonic and fetal beta-type globin genes in adult, which is elicited by TR2 and TR4.

  5. Development of novel therapeutic strategies for sickle cell disease by activating Nrf2

    Suzuki Mikiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    Sickle cell disease (SCD) is an inherited disease caused by a mutation in globin gene. Hemoglobins containing the mutated globin polymerize in red blood cells (RBC) and deform RBC into a sickle-like shape. The sickle-shaped RBCs are prone to intravascular hemolysis and intermittent blood glow occlusion, which results in ischemia-reperfusion injury generating oxidative stresses. Nrf2 is a transcription factor that induces expression of target genes involved in cellular defense against oxidative stresses. In this study, we found that genetic and pharmacologic activation of Nrf2 ameliorated tissue damages and inflammation in SCD model mice, indicating that Nrf2 activation relieves symptoms of SCD. Based on these results, we propose that Nrf2 is a therapeutic target for the treatment of SCD.

  6. Identification of leukemia-initiating cells in an inv(3)(q21q26) mouse model

    Yamamoto Masayuki, SUZUKI MIKIKO

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    Chromosomal translocation and inversion between 3q21 and 3q26 gives rise to acute myeloid leukemia with poor diagnosis. Overexpression of EVI1 gene located on 3q26 driven by GATA2 distal hematopoietic enhancer located on 3q21 is a major cause of leukemogenesis. We previously generated a transgenic mouse model (3q21q26 mouse) recapitulating inv(3)(q21q26) allele by linking two bacterial artificial chromosome clones. To identify leukemia-initiating cells in leukemia with inv(3)(q21q26), we analyzed the leukemic 3q21q26 mouse bone marrow cells. The 3q21q26 mice developed leukemia in which B cell marker B220+ and myeloid cell marker Gr1+ populations were expanded. In these leukemic cells, B220+/Gr1-/c-Kit+ cells exhibited blast-like morphology and have colony-forming ability. In addition, nude mice, into which B220+/Gr1-/c-Kit+ cells were transplanted, developed leukemia. These results indicate that B220+/Gr1-/cKit+ cells contained leukemia-initiating cells in the leukemic 3q21q26 mice.

  7. Regulation of Erythropoietin production and its roles on adult hematopoiesis

    MINEGISHI Naoko, SUZUKI Mikiko, HIRANO Ikuo, SUZUKI Norio, SOUMA Tomokazu, YAMAZAKI Shun

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2012/04/01 - 2016/03/31

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    Erythropoietin, secreted from adult kidney, is essential for erythropoiesis. We made ISAM (Inherited Super Anemic Mice), which exhibited Epo-deficient-anemia in their adulthood. We found the significantly decreased number of proerythroblasts and basophilic erythroblasts in their bone marrow, and several downstream-genes of Epo signals in bone marrow cells. Epo producing cells of ISAM were demonstrated as the cells expressing green fluorescence, among cortical fibroblasts in adult kidneys, and also in the portion of embryonic neural cells and neural crest cells. In the experimental fibrotic kidneys, Epo-producing cells transformed into myofibroblasts and halted Epo production. These changes were reversible. We have an impression that the inhibition of inflammatory signals might be a novel therapeutic strategy for renal fibrosis and renal anemia.

  8. Analysis of EVI1-expressing leukemia using inv(3)(q21;q26) model mice

    SUZUKI Mikiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    Chromosomal translocation and inversion between 3q21 and 3q26 result in misexpression of EVI1 gene on 3q26, which induces leukemogenesis with poor diagnosis. To examine the underlying mechanism of leukemogenesis, we generated a novel mouse model of EVI1-expressing leukemia (3q21q26 mice) harboring a transgene recapitulating the inverted allele by linking two bacterial artificial chromosome (BAC) clones. The 3q21q26 mice suffer from myeloid and lymphoid leukemia after 24 weeks of age. We discovered an abnormal CD34-high cell fraction specifically in the bone marrow of 3q21q26 mice, suggesting that these cells are associated with leukemia.

  9. Analysis of GATA2 gene regulation using bacterial artificial chromosome transgenic mice

    SUZUKI Mikiko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2010 - 2011

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    In this study, we demonstrated that a GATA binding element located at 77 kb upstream of Gata2 gene is an enhancer of Gata2 gene in hematopoietic progenitors using bacterial artificial chromosome(BAC)transgenic mice. The-77 enhancer is close to protooncogene EVI1 in translocated/inverted alleles between 3q21 and 3q26 in 3q21q26 syndrome. Therefore, we generated transgenic mice harboring a BAC transgene recapitulating the 3q21q26 inversion allele in order to examine contribution of the-77 enhancer to the EVI1 gene overexpression in 3q21q26 syndrome.

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