Updated on 2022/04/07

写真a

 
NOURA Mina
 
Organization
Graduate School of Medicine Assistant Professor
Undergraduate School
School of Health Sciences
Title
Assistant Professor

Degree 1

  1. 博士(人間健康科学) ( 2021.3   京都大学 ) 

Research Areas 2

  1. Life Science / Hematology and medical oncology

  2. Life Science / Cell biology

Research History 3

  1. Shubun University   Assistant

    2021.9

  2. Kyoto University   Researcher

    2020.4 - 2021.8

  3. 天理医療大学   医療学部臨床検査学科   助手

    2018.4 - 2020.3

Education 3

  1. 京都大学 医学研究科 人間健康科学系専攻 博士後期課程

    2018.4 - 2021.3

  2. 京都大学 医学研究科 人間健康科学系専攻 修士課程

    2016.4 - 2018.3

  3. 京都大学 医学部 人間健康科学科 検査技術科学専攻

    2012.4 - 2016.3

 

Papers 11

  1. Efficacy of a combination therapy targeting CDK4/6 and autophagy in a mouse xenograft model of t(8;21) acute myeloid leukemia. Reviewed International journal

    Hidemasa Matsuo, Kana Nakatani, Yutarou Harata, Moe Higashitani, Yuri Ito, Aina Inagami, Mina Noura, Tatsutoshi Nakahata, Souichi Adachi

    Biochemistry and biophysics reports   Vol. 27   page: 101099 - 101099   2021.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    One of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) is t(8;21). Although patients with t(8;21) AML have a more favorable prognosis than other cytogenetic subgroups, relapse is still common and novel therapeutic approaches are needed. A recent study showed that t(8;21) AML is characterized by CCND2 deregulation and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells. In this study, we examined the in vivo effects of co-inhibiting CDK4/6 and autophagy. We used a mouse model in which t(8;21)-positive Kasumi-1 cells were subcutaneously inoculated into NOD/Shi-scid IL2Rgnull mice. The mice were treated with the autophagy inhibitor chloroquine (CQ), a CDK4/6 inhibitor (either abemaciclib or palbociclib), or a CDK4/6 inhibitor plus CQ. After 20 days of treatment, tumor volume was measured, and immunostaining and transmission electron microscopy observations were performed. There was no change in tumor growth in CQ-treated mice. However, mice treated with a CDK4/6 inhibitor plus CQ had significantly less tumor growth than mice treated with a CDK4/6 inhibitor alone. CDK4/6 inhibitor treatment increased the formation of autophagosomes. The number of single-strand DNA-positive (apoptotic) cells was significantly higher in the tumors of mice treated with a CDK4/6 inhibitor plus CQ than in mice treated with either CQ or a CDK4/6 inhibitor. These results show that CDK4/6 inhibition induces autophagy, and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells in vivo. The results suggest that inhibiting CDK4/6 and autophagy could be a novel and promising therapeutic strategy in t(8;21) AML.

    DOI: 10.1016/j.bbrep.2021.101099

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  2. Albendazole induces the terminal differentiation of acute myeloid leukaemia cells to monocytes by stimulating the Krüppel-like factor 4-dihydropyrimidinase-like 2A (KLF4-DPYSL2A) axis. Reviewed International journal

    Mina Noura, Ken Morita, Hiroki Kiyose, Yukiko Okuno, Hidemasa Matsuo, Asami Koyama, Yoko Nishinaka-Arai, Yasuhiko Kamikubo, Souichi Adachi

    British journal of haematology   Vol. 194 ( 3 ) page: 598 - 603   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Differentiation therapy is a less toxic but still a very effective treatment for a subset of acute myeloid leukaemia (AML) cases. With the goal to identify novel compounds that can effectively and safely induce the terminal differentiation of non-acute promyelocytic leukaemia (APL) AML cells, we performed a chemical screening and identified albendazole (ABZ), a widely used anti-helminthic drug, as a promising lead compound that can differentiate non-APL AML cells by stimulating the Krüppel-like factor 4-dihydropyrimidinase-like 2A (KLF4-DPYSL2A) differentiation axis to the monocytes. Our in vitro and in vivo findings demonstrate that ABZ is an attractive candidate drug as a novel differentiation chemotherapy for patients with non-APL AML.

    DOI: 10.1111/bjh.17557

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  3. RUNX inhibitor suppresses graft‐versus‐host disease through targeting RUNX‐NFATC2 axis Reviewed

    Hirohito Kubota, Tatsuya Masuda, Mina Noura, Kana Furuichi, Hidemasa Matsuo, Masahiro Hirata, Tatsuki R. Kataoka, Hidefumi Hiramatsu, Takahiro Yasumi, Tatsutoshi Nakahata, Yoichi Imai, Junko Takita, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo

    eJHaem   Vol. 2 ( 3 ) page: 449 - 458   2021.8

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/jha2.230

    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jha2.230

  4. Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells. Reviewed

    Kana Nakatani, Hidemasa Matsuo, Yutarou Harata, Moe Higashitani, Asami Koyama, Mina Noura, Yoko Nishinaka-Arai, Yasuhiko Kamikubo, Souichi Adachi

    International journal of hematology   Vol. 113 ( 2 ) page: 243 - 253   2021.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    The t(8;21) translocation is the most common cytogenetic abnormality in acute myeloid leukemia (AML). Although t(8;21) AML patients have a relatively favorable prognosis, relapse is a frequent occurrence, underscoring the need to develop novel therapeutic approaches. Here, we showed that t(8;21) AML is characterized by frequent mutation and overexpression of CCND2. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for the selective CDK4/6 inhibitors palbociclib and abemaciclib than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. CDK4/6 inhibition decreased MAP-ERK and PI3K-AKT-mTOR signaling pathway activity, induced LC3B-I to LC3B-II conversion, and enhanced autophagosome formation, suggesting autophagy induction. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with the CDK4/6 inhibitor abemaciclib significantly increased the percentage of apoptotic (Annexin V positive) cells, whereas CQ or LY294002 single treatment had no significant effects. The effectiveness of co-inhibiting CDK4/6 and autophagy was confirmed in primary t(8;21) AML cells. The results suggest that the combination of CDK4/6 and autophagy inhibitors had a synergistic effect on inducing apoptosis, suggesting a novel therapeutic approach for the treatment of t(8;21) AML.

    DOI: 10.1007/s12185-020-03015-4

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  5. Suppression of malignant rhabdoid tumors through Chb-M'-mediated RUNX1 inhibition. Reviewed International journal

    Tomoo Daifu, Masamitsu Mikami, Hidefumi Hiramatsu, Atsushi Iwai, Katsutsugu Umeda, Mina Noura, Hirohito Kubota, Tatsuya Masuda, Kana Furuichi, Saho Takasaki, Yuki Noguchi, Ken Morita, Toshikazu Bando, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Yasumichi Kuwahara, Tomoko Iehara, Hajime Hosoi, Junko Takita, Hiroshi Sugiyama, Souichi Adachi, Yasuhiko Kamikubo

    Pediatric blood & cancer   Vol. 68 ( 2 ) page: e28789   2021.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy.

    DOI: 10.1002/pbc.28789

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  6. Pivotal role of DPYSL2A in KLF4-mediated monocytic differentiation of acute myeloid leukemia cells. Reviewed International journal

    Mina Noura, Ken Morita, Hiroki Kiyose, Hidemasa Matsuo, Yoko Nishinaka-Arai, Mineo Kurokawa, Yasuhiko Kamikubo, Souichi Adachi

    Scientific reports   Vol. 10 ( 1 ) page: 20245 - 20245   2020.11

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    Language:Japanese   Publisher:(一社)日本癌学会  

    Although the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML.

    DOI: 10.1038/s41598-020-76951-0

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  7. TXNIP induces growth arrest and enhances ABT263‐induced apoptosis in mixed‐lineage leukemia‐rearranged acute myeloid leukemia cells International journal

    Noura Mina, Matsuo Hidemasa, Koyama Asami, Adachi Souichi, Masutani Hiroshi

    FEBS Open Bio   Vol. 10 ( 8 ) page: 1532 - 1541   2020.8

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    Language:English   Publishing type:Research paper (scientific journal)  

    Thioredoxin‐interacting protein (TXNIP) has been widely recognized as a tumor suppressor in various cancers, including liver, breast, and thyroid cancers. Although TXNIP is epigenetically silenced in acute myeloid leukemia (AML) cells, as in many cancer cells, its role in leukemogenesis remains elusive. Mixed‐lineage leukemia (MLL) gene rearrangements in AML are associated with poor prognosis, and the development of a new treatment method is eagerly anticipated. In this study, we first reveal that lower expression of TXNIP is correlated with shortened overall survival periods in AML patients. Moreover, we demonstrated that TXNIP overexpression significantly suppresses proliferation in AML cells harboring MLL fusion genes. TXNIP promotes autophagy by increasing expression of the autophagy protein, Beclin 1, and lipidation of LC3B. We also show that TXNIP overexpression combined with ABT263, a potent inhibitor of Bcl‐2 and Bcl‐xL, is highly effective at inducing cell death in MLL‐rearranged (MLL‐r) AML cells. In summary, this study provides insights into the molecular mechanism of TXNIP‐mediated tumor suppression and furthermore underscores the potential of TXNIP as a promising therapeutic target for MLL‐r AML.

    DOI: 10.1002/2211-5463.12908

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  8. Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia International journal

    Matsuo Hidemasa, Yoshida Kenichi, Fukumura Kazutaka, Nakatani Kana, Noguchi Yuki, Takasaki Saho, Noura Mina, Shiozawa Yusuke, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Okada Ai, Nannya Yasuhito, Takeda June, Ueno Hiroo, Shiba Norio, Yamato Genki, Handa Hiroshi, Ono Yuichiro, Hiramoto Nobuhiro, Ishikawa Takayuki, Usuki Kensuke, Ishiyama Ken, Miyawaki Shuichi, Itonaga Hidehiro, Miyazaki Yasushi, Kawamura Machiko, Yamaguchi Hiroki, Kiyokawa Nobutaka, Tomizawa Daisuke, Taga Takashi, Tawa Akio, Hayashi Yasuhide, Mano Hiroyuki, Miyano Satoru, Kamikubo Yasuhiko, Ogawa Seishi, Adachi Souichi

    Blood Advances   Vol. 2 ( 21 ) page: 2879 - 2889   2018.11

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    In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3–rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.

    DOI: 10.1182/bloodadvances.2018019398

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  9. RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice. Reviewed International journal

    Ken Morita, Chieko Tokushige, Shintaro Maeda, Hiroki Kiyose, Mina Noura, Atsushi Iwai, Maya Yamada, Gengo Kashiwazaki, Junichi Taniguchi, Toshikazu Bando, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo

    Blood advances   Vol. 2 ( 5 ) page: 509 - 515   2018.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients.

    DOI: 10.1182/bloodadvances.2017009324

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  10. Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells. Reviewed International journal

    Ken Morita, Mina Noura, Chieko Tokushige, Shintaro Maeda, Hiroki Kiyose, Gengo Kashiwazaki, Junichi Taniguchi, Toshikazu Bando, Kenichi Yoshida, Toshifumi Ozaki, Hidemasa Matsuo, Seishi Ogawa, Pu Paul Liu, Tatsutoshi Nakahata, Hiroshi Sugiyama, Souichi Adachi, Yasuhiko Kamikubo

    Scientific reports   Vol. 7 ( 1 ) page: 16604 - 16604   2017.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.

    DOI: 10.1038/s41598-017-16799-z

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  11. Genetic regulation of the RUNX transcription factor family has antitumor effects. Reviewed International journal

    Ken Morita, Kensho Suzuki, Shintaro Maeda, Akihiko Matsuo, Yoshihide Mitsuda, Chieko Tokushige, Gengo Kashiwazaki, Junichi Taniguchi, Rina Maeda, Mina Noura, Masahiro Hirata, Tatsuki Kataoka, Ayaka Yano, Yoshimi Yamada, Hiroki Kiyose, Mayu Tokumasu, Hidemasa Matsuo, Sunao Tanaka, Yasushi Okuno, Manabu Muto, Kazuhito Naka, Kosei Ito, Toshio Kitamura, Yasufumi Kaneda, Paul P Liu, Toshikazu Bando, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo

    The Journal of clinical investigation   Vol. 127 ( 7 ) page: 2815 - 2828   2017.6

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    Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.

    DOI: 10.1172/JCI91788

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MISC 7

  1. Autophagy Inhibition Enhances CDK4/6 Inhibitor-Induced Apoptosis in t(8;21) Acute Myeloid Leukemia Cells

    Kana Nakatani, Hidemasa Matsuo, Yutarou Harata, Moe Higashitani, Asami Koyama, Mina Noura, Yoko Nishinaka-Arai, Yasuhiko Kamikubo, Souichi Adachi

      Vol. 136   2020.11

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    DOI: https://doi.org/10.1182/blood-2020-133881

  2. レンチウイルスベクターを用いた急性骨髄性白血病(AML)細胞株へのTXNIP遺伝子導入

    能浦 三奈, 増谷 弘

    天理医療大学紀要   Vol. 8 ( 1 ) page: 47 - 51   2020.3

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    Language:Japanese   Publisher:(学)天理よろづ相談所学園天理医療大学医療学部  

    急性骨髄性白血病(AML)は骨髄中で異常な芽球が増殖する悪性疾患である。AMLの治療成績は改善傾向にあるが、若年成人AML全体の5年無再発生存率は40%程度である。またAMLには様々なサブタイプが存在し、その治療感受性や予後は大きく異なることから、難治性AMLに対する新規治療法の開発が切望される。筆者は予後不良AMLの新規治療標的としてthioredoxin interacting protein(TXNIP)に注目した。TXNIPは様々ながんで発現低下が報告されているが、その詳細な分子機構はほとんど解明されていない。本研究ではAMLにおけるTXNIPの機能解析を目的とし、レンチウイルスベクターによるAML細胞株への遺伝子導入を行った。(著者抄録)

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J06660&link_issn=&doc_id=20201015460006&doc_link_id=10.24667%2Fthcu.8.1_47&url=https%3A%2F%2Fdoi.org%2F10.24667%2Fthcu.8.1_47&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  3. Recurrent Genomic Aberrations of D-Type Cyclins Are Therapeutic Targets of CDK4/6 Inhibitors in t(8;21) and MLL-Rearranged Acute Myeloid Leukemia

    Hidemasa Matsuo, Kenichi Yoshida, Kazutaka Fukumura, Kana Nakatani, Yuki Noguchi, Saho Takasaki, Mina Noura, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Ai Okada, Yasuhito Nannya, June Takeda, Hiroo Ueno, Norio Shiba, Genki Yamato, Hiroshi Handa, Yuichiro Ono, Nobuhiro Hiramoto, Takayuki Ishikawa, Kensuke Usuki, Ken Ishiyama, Shuichi Miyawaki, Hidehiro Itonaga, Yasushi Miyazaki, Machiko Kawamura, Hiroki Yamaguchi, Nobutaka Kiyokawa, Daisuke Tomizawa, Takashi Taga, Akio Tawa, Yasuhide Hayashi, Hiroyuki Mano, Satoru Miyano, Yasuhiko Kamikubo, Seishi Ogawa, Souichi Adachi

    BLOOD   Vol. 132   2018.11

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    DOI: 10.1182/blood-2018-99-111073

  4. AMLの新規治療 CROX:(Cluster Regulation of RUNX)による新規急性骨髄性白血病制御戦略の提唱

    野口 勇貴, 能浦 三奈, 岩井 詩咲花, 嶌田 紗英, 鈴木 雄太, 杉山 弘, 足立 壮一, 上久保 靖彦

    日本小児血液・がん学会雑誌   Vol. 55 ( 3 ) page: 223 - 228   2018.10

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    Language:Japanese   Publisher:(一社)日本小児血液・がん学会  

    Runt-related transcription factor(RUNX)はRUNX1、RUNX2、RUNX3の3つのファミリーからなる転写因子である。従来"がん抑制遺伝子"と認識されていたが、近年はむしろそのオンコジェニックな側面(腫瘍増殖促進、癌幹細胞維持、薬剤耐性獲得など)が注目されつつあり、様々な癌の特質となるHallmarksに関わる主要因子と深く関連していることが明らかになりつつある。我々のグループは、世界に先駆けてこのRUNXのオンコジェニックメカニズムの解明とそれをターゲットとする制御戦略を構築中である。我々は、RUNX familyに共通するconsensus binding sequence(5'-TGTGGT-3')に着目し、これを阻害できる薬剤であるChlorambucil-conjugated pyrrole imidazole polyamide(Chb-M')を開発中である。本稿では、第59回日本小児血液・がん学会学術集会AMLシンポジウムで発表した議題を中心に、新薬開発基盤となる急性骨髄性白血病(AML)の増殖性維持機構、薬剤耐性獲得機構をそのメカニズムの一端と、我々の遺伝子スイッチ法を用いた新規制御コンセプトを述べたい。(著者抄録)

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J06030&link_issn=&doc_id=20190121410002&doc_link_id=%2Fex9syoga%2F2018%2F005503%2F002%2F0223-0228%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fex9syoga%2F2018%2F005503%2F002%2F0223-0228%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  5. AML細胞のRUNX1-p53-CBFBフィードバックループによる薬剤耐性化

    能浦 三奈, 足立 壮一, 杉山 弘, 上久保 靖彦

    血液内科   Vol. 77 ( 2 ) page: 254 - 259   2018.8

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  6. Cell-Autonomous Feedback Loop of RUNX1-p53-CBFB in Acute Myeloid Leukemia Cells

    Mina Noura, Ken Morita, Chieko Tokushige, Shintaro Maeda, Hiroki Kiyose, Toshikazu Bando, Kenichi Yoshida, Hidemasa Matsuo, Seishi Ogawa, Paul P. Liu, Hiroshi Sugiyama, Yasuhiko Kamikubo, Souichi Adachi

    BLOOD   Vol. 130   2017.12

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:AMER SOC HEMATOLOGY  

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  7. RUNX1 Enhances Leukemia Cell Engraftment in the Vascular Niche through up-Regulating E-Selectin

    Chieko Tokushige, Ken Morita, Shintaro Maeda, Hiroki Kiyose, Mina Noura, Tatsuki Kataoka, Toshikazu Bando, Hiroshi Sugiyama, Yasuhiko Kamikubo, Souichi Adachi

    BLOOD   Vol. 130   2017.12

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:AMER SOC HEMATOLOGY  

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KAKENHI (Grants-in-Aid for Scientific Research) 1

  1. 急性骨髄性白血病(AML)におけるTXNIPによるオートファジー制御機構の解明

    Grant number:19K17875  2019.4 - 2022.3

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    能浦 三奈

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    申請者の研究室で報告されたThioredoxin interacting protein (TXNIP)は肝がん、乳がん、甲状腺がんなど様々ながんで発現低下が報告されている。AMLにおいてもエピジェネティクス異常により発現が低下しているが、白血病発症との関連性は不明である。本年度は臨床検体データベースを用いて予後解析を行うと共に、AMLのサブタイプごとのTXNIP発現量を明らかにした。これまでAMLにおけるTXNIPの発現低下が複数報告されているが、実際にはすべてのAMLで発現が低下しているわけではなく、サブタイプによって発現量が大きく異なることを明らかにした。申請者はTXNIPの発現が最も著しく低下しているMixed-lineage leukemia (MLL)遺伝子再構成を伴うAMLに注目した。MLL遺伝子再構成陽性AML細胞株で予後不良因子FLT3-ITDを有するMOLM-13およびMV4-11にテトラサイクリン誘導性TXNIP過剰発現ベクターを導入したところ、両細胞株において細胞増殖が有意に抑制された。TXNIPによる抗腫瘍メカニズムを明らかにするため、細胞周期解析を行ったが、有意な差は認められなかった。アポトーシスアッセイにおいても有意な差は認められなかったが、TXNIP過剰発現下では細胞膜の透過性が亢進していることを示す知見が得られた。さらにTXNIPは飢餓応答や糖代謝、アミノ酸代謝を制御することから、TXNIPによるオートファジー誘導の関与について検討した。TXNIP過剰発現AML細胞ではオートファジー関連蛋白が増加し、オートファゴソームが形成されることを明らかにした。