九州大学 研究者情報
論文一覧
前田 高宏(まえだ たかひろ) データ更新日:2022.06.30

教授 /  医学研究院 附属プレシジョンメディシン研究センター プレシジョン医療学


原著論文
1. Jake C Swartzel, Michael J Bond, Andreas P Pintado-Urbanc, Mehana Daftary, Mackenzie W Krone, Todd Douglas, Evan J Carder, Joshua T Zimmer, Takahiro Maeda, Matthew D Simon, Craig M Crews, Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC, ACS Chem Biol, 10.1021/acschembio.2c00145, 2022.06, The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders..
2. Kohta Miyawaki, Koji Kato, Takeshi Sugio, Kensuke Sasaki, Hiroaki Miyoshi, Yuichiro Semba, Yoshikane Kikushige, Yasuo Mori, Yuya Kunisaki, Hiromi Iwasaki, Toshihiro Miyamoto, Frank C Kuo, Jon C. Aster, Koichi Ohshima, Takahiro Maeda, Koichi Akashi, A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL, Blood Advances, 10.1182/bloodadvances.2021004618, 2021.10, Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures..
3. Ikumi Yamanaka, Takuji Yamauchi, Tomoko Henzan, Teppei Sakoda, Kyoko Miyamoto, Hiroyuki Mishima, Hiroaki Ono, Yuhki Koga, Yasuhiro Nakashima, Koji Kato, Toshihiro Miyamoto, Shinichi Mizuno, Yoshihiro Ogawa, Shouichi Ohga, Koichi Akashi, Takahiro Maeda, Yuya Kunisaki, Optimization of lymphapheresis for manufacturing autologous CAR-T cells, International Journal of Hematology, 10.1007/s12185-021-03191-x, 114, 4, 449-458, 2021.10.
4. Kensuke Sasaki, Takuji Yamauchi, Yuichiro Semba, Jumpei Nogami, Hiroshi Imanaga, Tatsuya Terasaki, Fumihiko Nakao, Koshi Akahane, Takeshi Inukai, ELs Verhoeyen, Koichi Akashi, Takahiro Maeda, Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL, Blood, 10.1182/blood.2021012976, 2021.09, Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes..
5. Tomoko Henzan, Takuji Yamauchi, Ikumi Yamanaka, Teppei Sakoda, Yuichiro Semba, Masayasu Hayashi, Yoshikane Kikushige, Hiroyuki Mishima, Masataka Ishimura, Yuhki Koga, Toshihiro Miyamoto, Shouichi Ohga, Koichi Akashi, Takahiro Maeda, Yuya Kunisaki, Granulocyte collection by polymorphonuclear cell-targeting apheresis with medium-molecular-weight hydroxyethyl starch, International Journal of Hematology, 10.1007/s12185-021-03207-6, 2021.08.
6. Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Masatomo Takahashi, Yoshihiro Izumi, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki, Luca Pinello, Daniel E. Bauer, Takeshi Bamba, Koichi Akashi, Takahiro Maeda, Targeting leukemia-specific dependence on the de novo purine synthesis pathway, Leukemia, 10.1038/s41375-021-01369-0, 2021.08.
7. Takahiro Shima, Teppei Sakoda, Tomoko Henzan, Yuya Kunisaki, Takeshi Sugio, Kenjiro Kamezaki, Hiromi Iwasaki, Takanori Teshima, Takahiro Maeda, Koichi Akashi, Toshihiro Miyamoto, Platelet decrease and efficacy of platelet‐rich plasma return following peripheral blood stem cell apheresis, Journal of Clinical Apheresis, 10.1002/jca.21917, 2021.06.
8. Satoshi Morishige, Toshihiro Miyamoto, Tetsuya Eto, Naoyuki Uchida, Tomohiko Kamimura, Yasuhiko Miyazaki, Ryosuke Ogawa, Hirokazu Okumura, Tomoaki Fujisak, Hiromi Iwasaki, Noriaki Kawano, Atsushi Wake, Takanori Ohta, Yasushi Takamatsu, Toshiro Kurokawa, Yoshikiyo Ito, Takahiro Maeda, Koichi Akashi, Koji Nagafuji, Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008, International Journal of Hematology, 10.1007/s12185-021-03116-8, 2021.03.
9. Kuniko Sunami, Yoichi Naito, Eriko Aimono, Toraji Amano, Daisuke Ennishi, Hidenori Kage, Masashi Kanai, Keigo Komine, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Shinji Kohsaka, Katsuya Tsuchihara, Takayuki Yoshino, The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan, International Journal of Clinical Oncology, 10.1007/s10147-020-01844-1, 26, 3, 443-449, 2021.03, Abstract
Background
Since June 2019, cancer genomic profiling (CGP) tests have been reimbursed by the National Health Insurance system in Japan, with restrictions for government-designated hospitals with a molecular tumor board composed of multidisciplinary specialists, known as an expert panel (EP). The standardization of EPs is a critical challenge for implementing precision oncology in the clinical setting.



Methods
Data on consecutive cases who underwent the CGP tests at 11 core hospitals between June 2019 and January 2020 were collected. We evaluated the proportions of cases that received genomically matched treatments, including investigational new drugs (INDs) based on CGP results, and/or for which genetic counseling was recommended. Two simulated cases were annotated by each EP. The annotated reports were then centrally assessed.



Results
Each EP mainly discussed the applicability to genomically matched treatments and the necessity of performing genetic counseling. A pre-review of the report by key members in each EP reportedly made the EP conference more interactive and efficient, and thereby saved time. A total of 747 cases underwent CGP tests, 28 cases (3.7%) received genomically matched treatment, and 17 cases (2.3%) were referred for genetic counseling. Annotated reports for the simulated cases varied across the EPs, particularly the number of recommended IND trials, which seemed to be associated with the actual number of participants in IND trials.



Conclusions
This investigation provides reference data for the application of precision oncology in a clinical setting. Further investigations on the standardization of clinical annotations are warranted.


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10. Shuki Oya, Satoshi Morishige, Hidetoshi Ozawa, Kensuke Sasaki, Yuichiro Semba, Yoshitaka Yamasaki, Takayuki Nakamura, Kazutoshi Aoyama, Ritsuko Seki, Fumihiko Mouri, Koichi Osaki, Toshihiro Miyamoto, Takahiro Maeda, Koji Nagafuji, Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion, International Journal of Hematology, 10.1007/s12185-020-03006-5, 113, 2, 285-289, 2021.02.
11. Yasuo Mori, Kensuke Sasaki, Yoshikiyo Ito, Takuro Kuriyama, Toshiyuki Ueno, Masanori Kadowaki, Takatoshi Aoki, Takeshi Sugio, Goichi Yoshimoto, Koji Kato, Takahiro Maeda, Koji Nagafuji, Koichi Akashi, Toshihiro Miyamoto, Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study, Annals of Hematology, 10.1007/s00277-020-04310-0, 100, 1, 197-208, 2021.01.
12. Taro Tochigi, Toshihiro Miyamoto, Kiwamu Hatakeyama, Teppei Sakoda, Daisuke Ishihara, Hidetoshi Irifune, Takahiro Shima, Koji Kato, Takahiro Maeda, Takumi Ito, Hiroshi Handa, Koichi Akashi, Yoshikane Kikushige, Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug–induced thrombocytopenia, Blood, 10.1182/blood.2019003749, 135, 24, 2146-2158, 2020.06, Abstract
Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia..
13. Fumiaki Jinnouchi, Takuji Yamauchi, Ayano Yurino, Takuya Nunomura, Michitaka Nakano, Chika Iwamoto, Teppei Obara, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Katsuto Takenaka, A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells, Blood, 10.1182/blood.2019002194, 135, 19, 1661-1672, 2020.05, Abstract
In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa−/− mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells..
14. Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi, Anti-GPRC5D/CD3 Bispecific T-Cell–Redirecting Antibody for the Treatment of Multiple Myeloma, Molecular Cancer Therapeutics, 10.1158/1535-7163.mct-18-1216, 18, 9, 1555-1564, 2019.09.
15. Mariko Minami, Takumi Matsushima, Yasuo Mori, Daisuke Ishihara, Fumiaki Jinnnouchi, Katsuto Takenaka, Tomoko Henzan, Goichi Yoshimoto, Akihiko Numata, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Koichi Akashi, Successful rescue transplantation with desensitization procedure after primary graft failure due to donor-specific antibody, Bone Marrow Transplantation, 10.1038/s41409-019-0486-4, 54, 8, 1374-1376, 2019.08.
16. Falak Sher, Mir Hossain, Davide Seruggia, Vivien A. C. Schoonenberg, Qiuming Yao, Paolo Cifani, Laura M. K. Dassama, Mitchel A. Cole, Chunyan Ren, Divya S. Vinjamur, Claudio Macias-Trevino, Kevin Luk, Connor McGuckin, Patrick G. Schupp, Matthew C. Canver, Ryo Kurita, Yukio Nakamura, Yuko Fujiwara, Scot A. Wolfe, Luca Pinello, Takahiro Maeda, Alex Kentsis, Stuart H. Orkin, Daniel E. Bauer, Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis, Nature Genetics, 10.1038/s41588-019-0453-4, 51, 7, 1149-1159, 2019.07.
17. Matthew C Canver, Daniel E Bauer, Takahiro Maeda, Luca Pinello, DrugThatGene: integrative analysis to streamline the identification of druggable genes, pathways and protein complexes from CRISPR screens, Bioinformatics, 10.1093/bioinformatics/bty913, 35, 11, 1981-1984, 2019.06.
18. Shinichi Kotani, Akinori Yoda, Ayana Kon, Keisuke Kataoka, Yotaro Ochi, Yusuke Shiozawa, Cassandra Hirsch, June Takeda, Hiroo Ueno, Tetsuichi Yoshizato, Kenichi Yoshida, Masahiro M. Nakagawa, Yasuhito Nannya, Nobuyuki Kakiuchi, Takuji Yamauchi, Kosuke Aoki, Yuichi Shiraishi, Satoru Miyano, Takahiro Maeda, Jaroslaw P. Maciejewski, Akifumi Takaori-Kondo, Seishi Ogawa, Hideki Makishima, Molecular pathogenesis of disease progression in MLL-rearranged AML, Leukemia, 10.1038/s41375-018-0253-3, 33, 3, 612-624, 2019.03.
19. Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi, Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer, Oncogene, 10.1038/s41388-018-0480-0, 38, 6, 780-793, 2019.02.
20. Yasuo Mori, Goichi Yoshimoto, Jun-Ichiro Yuda, Masayasu Hayashi, Jun Odawara, Takuro Kuriyama, Takeshi Sugio, Kohta Miyawaki, Kenjiro Kamezaki, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Takahiro Maeda, Toshihiro Miyamoto, Koichi Akashi, Previous exposure to bortezomib is linked to a lower risk of engraftment syndrome after autologous hematopoietic stem cell transplantation, Leukemia & Lymphoma, 10.1080/10428194.2018.1466295, 60, 1, 271-273, 2019.01.
21. Vivien A. C. Schoonenberg, Mitchel A. Cole, Qiuming Yao, Claudio Macias-Treviño, Falak Sher, Patrick G. Schupp, Matthew C. Canver, Takahiro Maeda, Luca Pinello, Daniel E. Bauer, CRISPRO: identification of functional protein coding sequences based on genome editing dense mutagenesis, Genome Biology, 10.1186/s13059-018-1563-5, 19, 1, 2018.12.
22. Goichi Yoshimoto, Yasuo Mori, Koji Kato, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Kenjiro Kamezaki, Akihiko Numata, Takahiro Maeda, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Toshihiro Miyamoto, Human Herpes Virus-6–Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor–Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients, Biology of Blood and Marrow Transplantation, 10.1016/j.bbmt.2018.07.017, 24, 12, 2540-2548, 2018.12.
23. Yasuo Mori, Goichi Yoshimoto, Ruriko Nishida, Takeshi Sugio, Kohta Miyawaki, Takahiro Shima, Yoji Nagasaki, Noriko Miyake, Yukiko Harada, Yuya Kunisaki, Kenjiro Kamezaki, Akihiko Numata, Koji Kato, Motoaki Shiratsuchi, Takahiro Maeda, Katsuto Takenaka, Hiromi Iwasaki, Nobuyuki Shimono, Koichi Akashi, Toshihiro Miyamoto, Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients, Biology of Blood and Marrow Transplantation, 10.1016/j.bbmt.2018.06.002, 24, 11, 2302-2309, 2018.11.
24. Takeshi Sugio, Kohta Miyawaki, Koji Kato, Kensuke Sasaki, Kyohei Yamada, Javeed Iqbal, Toshihiro Miyamoto, Koichi Ohshima, Takahiro Maeda, Hiroaki Miyoshi, Koichi Akashi, Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS, Blood Advances, 10.1182/bloodadvances.2018018754, 2, 17, 2242-2252, 2018.09, Key Points
Microenvironmental immune cell signatures stratify PTCL-NOS patients into clinically meaningful disease subtypes. Immune-checkpoint inhibitors represent potential therapeutic options for a PTCL-NOS patient subgroup..
25. Kensuke Sasaki, Yasuo Mori, Goichi Yoshimoto, Teppei Sakoda, Koji Kato, Kyoko Inadomi, Kenjiro Kamezaki, Katsuto Takenaka, Hiromi Iwasaki, Takahiro Maeda, Toshihiro Miyamoto, Koichi Akashi, Successful treatment of Ph ALL with hematopoietic stem cell transplantation from the same HLA-haploidentical related donor of previous liver transplantation, Leukemia & Lymphoma, 10.1080/10428194.2017.1403021, 59, 8, 2005-2007, 2018.08.
26. Takuji Yamauchi, Takeshi Masuda, Matthew C. Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A.C. Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H. Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi Akashi, Daniel E. Bauer, Takahiro Maeda, Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS, Cancer Cell, 10.1016/j.ccell.2018.01.012, 33, 3, 386-400.e5, 2018.03.
27. Kohta Miyawaki, Hiromi Iwasaki, Takashi Jiromaru, Hirotake Kusumoto, Ayano Yurino, Takeshi Sugio, Yasufumi Uehara, Jun Odawara, Shinya Daitoku, Yuya Kunisaki, Yasuo Mori, Yojiro Arinobu, Hirofumi Tsuzuki, Yoshikane Kikushige, Tadafumi Iino, Koji Kato, Katsuto Takenaka, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi, Identification of unipotent megakaryocyte progenitors in human hematopoiesis, Blood, 10.1182/blood-2016-09-741611, 129, 25, 3332-3343, 2017.06, Publisher's Note: There is an Inside Blood Commentary on this article in this issue..
28. Jacky Chung, Johannes G Wittig, Alireza Ghamari, Manami Maeda, Tamara A Dailey, Hector Bergonia, Martin D Kafina, Emma E Coughlin, Catherine E Minogue, Alexander S Hebert, Liangtao Li, Jerry Kaplan, Harvey F Lodish, Daniel E Bauer, Stuart H Orkin, Alan B Cantor, Takahiro Maeda, John D Phillips, Joshua J Coon, David J Pagliarini, Harry A Dailey, Barry H Paw, Erythropoietin signaling regulates heme biosynthesis, eLife, 10.7554/elife.24767, 6, 2017.05, Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development..
29. Takeshi Masuda, Xin Wang, Manami Maeda, Matthew C. Canver, Falak Sher, Alister P. W. Funnell, Chris Fisher, Maria Suciu, Gabriella E. Martyn, Laura J. Norton, Catherine Zhu, Ryo Kurita, Yukio Nakamura, Jian Xu, Douglas R. Higgs, Merlin Crossley, Daniel E. Bauer, Stuart H. Orkin, Peter V. Kharchenko, Takahiro Maeda, Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin, Science, 10.1126/science.aad3312, 351, 6270, 285-289, 2016.01.
30. Leonor Gama-Norton, Eva Ferrando, Cristina Ruiz-Herguido, Zhenyi Liu, Jordi Guiu, Abul B. M. M. K. Islam, Sung-Uk Lee, Minhong Yan, Cynthia J. Guidos, Nuria López-Bigas, Takahiro Maeda, Lluis Espinosa, Raphael Kopan, Anna Bigas, Notch signal strength controls cell fate in the haemogenic endothelium, Nature Communications, 10.1038/ncomms9510, 6, 1, 2015.12, Abstract
Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta–gonad–mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage..
31. Matthew C. Canver, Elenoe C. Smith, Falak Sher, Luca Pinello, Neville E. Sanjana, Ophir Shalem, Diane D. Chen, Patrick G. Schupp, Divya S. Vinjamur, Sara P. Garcia, Sidinh Luc, Ryo Kurita, Yukio Nakamura, Yuko Fujiwara, Takahiro Maeda, Guo-Cheng Yuan, Feng Zhang, Stuart H. Orkin, Daniel E. Bauer, BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis, Nature, 10.1038/nature15521, 527, 7577, 192-197, 2015.11.
32. Zhen Zhao, Abhay P Sagare, Qingyi Ma, Matthew R Halliday, Pan Kong, Kassandra Kisler, Ethan A Winkler, Anita Ramanathan, Takahisa Kanekiyo, Guojun Bu, Nelly Chuqui Owens, Sanket V Rege, Gabriel Si, Ashim Ahuja, Donghui Zhu, Carol A Miller, Julie A Schneider, Manami Maeda, Takahiro Maeda, Tohru Sugawara, Justin K Ichida, Berislav V Zlokovic, Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance, Nature Neuroscience, 10.1038/nn.4025, 18, 7, 978-987, 2015.07.
33. Jlenia Guarnerio, Luisa Riccardi, Riccardo Taulli, Takahiro Maeda, Guocan Wang, Robin M. Hobbs, Min Sup Song, Paolo Sportoletti, Rosa Bernardi, Roderick T. Bronson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Andrea Lunardi, Pier Paolo Pandolfi, A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells, Cancer Discovery, 10.1158/2159-8290.cd-14-1022, 5, 4, 396-409, 2015.04.
34. Y. Ishikawa, M. Maeda, M. Pasham, F. Aguet, S. K. Tacheva-Grigorova, T. Masuda, H. Yi, S.-U. Lee, J. Xu, J. Teruya-Feldstein, M. Ericsson, A. Mullally, J. Heuser, T. Kirchhausen, T. Maeda, Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology, Haematologica, 10.3324/haematol.2014.119537, 100, 4, 439-451, 2015.04.
35. Matthew C. Canver, Daniel E. Bauer, Abhishek Dass, Yvette Y. Yien, Jacky Chung, Takeshi Masuda, Takahiro Maeda, Barry H. Paw, Stuart H. Orkin, Characterization of Genomic Deletion Efficiency Mediated by Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 Nuclease System in Mammalian Cells*, Journal of Biological Chemistry, 10.1074/jbc.m114.564625, 289, 31, 21312-21324, 2014.08.
36. Olga Bohn, Takahiro Maeda, Alexander Filatov, Andrea Lunardi, Pier Paolo Pandolfi, Julie Teruya-Feldstein, Utility of LRF/Pokemon and NOTCH1 Protein Expression in the Distinction Between Nodular Lymphocyte-Predominant Hodgkin Lymphoma and Classical Hodgkin Lymphoma, International Journal of Surgical Pathology, 10.1177/1066896913513833, 22, 1, 6-11, 2014.02, Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) are considered separate entities with different prognosis and treatment. However, morphologic features can be similar and immunohistochemical studies are essential in the distinction; thus, determination of additional biomarkers is of utmost importance. LRF/Pokemon is a proto-oncogene, an interacting partner co-expressed with BCL6 in germinal centers and highly expressed in diffuse large B-cell lymphoma and follicular lymphoma. Conversely, loss of the LRF gene in mouse hematopoietic stem cells results in complete block of early B cell development with concomitant Notch de-repression, indicating its critical role in B versus T cell fate decision at the hematopoietic stem cell stage. For the first time, we show that LRF/Pokemon is predominantly expressed in NLPHL cases as is BCL6 with low to absent NOTCH1 protein expression; while Hodgkin Reed-Sternberg (HRS) cells in CHL show low to absent BCL6 and LRF/Pokemon expression with higher NOTCH1 expression. We illustrate a potential functional interaction between LRF and BCL6 in NLPHL pathogenesis, and differential expression of LRF/Pokemon and NOTCH1 proteins in CHL thus showing differential expression, making for an additional diagnostic marker and therapeutic target..
37. Caiyong Chen, Daniel Garcia-Santos, Yuichi Ishikawa, Alexandra Seguin, Liangtao Li, Katherine H. Fegan, Gordon J. Hildick-Smith, Dhvanit I. Shah, Jeffrey D. Cooney, Wen Chen, Matthew J. King, Yvette Y. Yien, Iman J. Schultz, Heidi Anderson, Arthur J. Dalton, Matthew L. Freedman, Paul D. Kingsley, James Palis, Shilpa M. Hattangadi, Harvey F. Lodish, Diane M. Ward, Jerry Kaplan, Takahiro Maeda, Prem Ponka, Barry H. Paw, Snx3 Regulates Recycling of the Transferrin Receptor and Iron Assimilation, Cell Metabolism, 10.1016/j.cmet.2013.01.013, 17, 3, 343-352, 2013.03.
38. Sung-Uk Lee, Manami Maeda, Yuichi Ishikawa, Sierra Min Li, Anne Wilson, Adrian M. Jubb, Nagisa Sakurai, Lihong Weng, Emma Fiorini, Freddy Radtke, Minhong Yan, H. Robson MacDonald, Ching-Cheng Chen, Takahiro Maeda, LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance, Blood, 10.1182/blood-2012-03-418103, 121, 6, 918-929, 2013.02, Key Points
Notch1/DII4-mediated signals are normally suppressed by LRF, preventing HSCs from premature T-cell differentiation in the bone marrow. Erythroblastic islands may have the capacity to regulate the fate and function of HSCs..
39. Bin Zhang, Yin Wei Ho, Qin Huang, Takahiro Maeda, Allen Lin, Sung-uk Lee, Alan Hair, Tessa L. Holyoake, Claudia Huettner, Ravi Bhatia, Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia, Cancer Cell, 10.1016/j.ccr.2012.02.018, 21, 4, 577-592, 2012.04.
40. K. Tsuji-Takechi, T. Negishi-Koga, E. Sumiya, A. Kukita, S. Kato, T. Maeda, P. P. Pandolfi, K. Moriyama, H. Takayanagi, Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development, Proceedings of the National Academy of Sciences, 10.1073/pnas.1116042109, 109, 7, 2561-2566, 2012.02.
41. Nagisa Sakurai, Manami Maeda, Sung-Uk Lee, Yuichi Ishikawa, Min Li, John C. Williams, Lisheng Wang, Leila Su, Mai Suzuki, Toshiki I. Saito, Shigeru Chiba, Stefano Casola, Hideo Yagita, Julie Teruya-Feldstein, Shinobu Tsuzuki, Ravi Bhatia, Takahiro Maeda, The LRF transcription factor regulates mature B cell development and the germinal center response in mice, Journal of Clinical Investigation, 10.1172/jci45682, 121, 7, 2583-2598, 2011.07.
42. Takahiro Maeda, Keisuke Ito, Taha Merghoub, Laura Poliseno, Robin M. Hobbs, Guocan Wang, Lin Dong, Manami Maeda, Louis C. Dore, Arthur Zelent, Lucio Luzzatto, Julie Teruya-Feldstein, Mitchell J. Weiss, Pier Paolo Pandolfi, LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis, Developmental Cell, 10.1016/j.devcel.2009.09.005, 17, 4, 527-540, 2009.10.
43. Takahiro Maeda, Taha Merghoub, Robin M. Hobbs, Lin Dong, Manami Maeda, Johannes Zakrzewski, Marcel R.M. van den Brink, Arthur Zelent, Hirokazu Shigematsu, Koichi Akashi, Julie Teruya-Feldstein, Giorgio Cattoretti, Pier Paolo Pandolfi, Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF, Science, 10.1126/science.1140881, 316, 5826, 860-866, 2007.05.
44. Takahiro Maeda, Robin M. Hobbs, Taha Merghoub, Ilhem Guernah, Arthur Zelent, Carlos Cordon-Cardo, Julie Teruya-Feldstein, Pier Paolo Pandolfi, Role of the proto-oncogene Pokemon in cellular transformation and ARF repression, Nature, 10.1038/nature03203, 433, 7023, 278-285, 2005.01.
45. Yukiyasu Ozawa, Masayuki Towatari, Shinobu Tsuzuki, Fumihiko Hayakawa, Takahiro Maeda, Yasuhiko Miyata, Mitsune Tanimoto, Hidehiko Saito, Histone deacetylase 3 associates with and represses the transcription factor GATA-2, Blood, 10.1182/blood.v98.7.2116, 98, 7, 2116-2123, 2001.10, The zinc finger transcription factor GATA-2 plays a critical role in the survival and proliferation of hematopoietic stem cells. This study examined the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly associates with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2–dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly associated with HDAC5 but not with other class II HDACs examined, that is, HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members..
46. Yasuhiko Miyata, Masayuki Towatari, Takahiro Maeda, Yukiyasu Ozawa, Hidehiko Saito, Histone Acetylation Induced by Granulocyte Colony-Stimulating Factor in a MAP Kinase-Dependent Manner, Biochemical and Biophysical Research Communications, 10.1006/bbrc.2001.4840, 283, 3, 655-660, 2001.05.
47. Takahiro Maeda, Masayuki Towatari, Hiroshi Kosugi, Hidehiko Saito, Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells., Blood, 96, 12, 3847-3856, 2000.12, Histone deacetylase inhibitors (HDACIs) have been used to focus on the effects of inducing gene expression through the acetylation of histones which results in chromatin remodeling. The study explored whether HDACIs could induce the expression of costimulatory/adhesion molecules on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. The expression of CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, and intracellular adhesion molecule-1 (ICAM-1) was tested in human AML cell lines after the addition of HDACI, sodium butyrate (SB). Generally, increased expression of CD86 was observed by SB treatment in a majority of cell lines, and ICAM-1 was expressed in fewer cell lines. Essentially the same results were obtained using other HDACIs such as FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 accompanied with RNA synthesis inhibition assay and nuclear run-on assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunoprecipitation experiments showed that HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In 30 clinical AML samples, CD86 expression was significantly increased (P <.001) by SB treatment, and the expression of HLA-DR and ICAM-1 was moderately increased (P <.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold compared with allo-MLR obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML. (Blood. 2000;96:3847-3856).

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