Identification of the mechanism of anti-tumor effect of IFN-alpha against malignant stem cells using iPS cells

• Project/Area Number: 19K17871
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Juntendo University
• Principal Investigator: Edahiro Yoko 順天堂大学, 医学部, 准教授 (40732863)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄増殖性腫瘍 / JAK2V617F / JAK2V617F変異 / iPS細胞 / インターフェロン

Outline of Research at the Start

骨髄増殖性腫瘍（myeloproliferative neoplasms: MPN）は、造血器腫瘍の一つであり、血液細胞の増加を認め、その結果血栓症などを起こす疾患である。MPNに対する根本的な治療法は、これまでリスクが高い骨髄移植のみとされてきたが、近年、一部のMPN患者ではインターフェロン-α(IFN-α)により、病気が完治することが明らかになってきた。しかし、なぜIFN-αが効くのか、その明確な機序は未だ明らかでない。本研究では、MPN患者由来のiPS細胞を作製し、試験管内において、IFN-αによる抗腫瘍作用の機序を解明することを目的とする。

Outline of Final Research Achievements

hiladelphia-negative myeloproliferative neoplasms (MPNs) are characterized by the clonal proliferation of hematopoietic stem and progenitor cells, driven by somatic mutations including JAK2V617F. Recently, some patients have been reported to achieve complete molecular remission by interferon-alpha (IFN-α), however its mechanism is not fully understood. In this study, I generated iPS cells from a patient with MPN and established an in vitro model system. Consequently, I added IFN-α to these iPS cells and analyzed the anti-tumor effect of IFN-α against MPN cells.

Academic Significance and Societal Importance of the Research Achievements

骨髄増殖性腫瘍（MPN）に対して、病気を完全に治癒させる可能性があるインターフェロン-α(IFN-α)の作用機序を、iPS細胞を用いて解析した。今回の研究では、JAK2V617F変異を導入したiPS細胞と、変異を有さない野生型のiPS細胞の両者で、血液細胞に対するIFN-αの効果を認めたが、明らかな差は認めなかった。今後、さらなる解析を行うことで、MPNの治癒を目指した治療戦略の構築につながると考える。

Research Products

• [Journal Article] Validation and reliability of current guidelines for the treatment of essential thrombocythemia under real-world clinical settings in Japan (2022)
  • Author(s): Baba Terumi、Hashimoto Yoshinori、Yasuda Hajime、Araki Marito、Edahiro Yoko、Morishita Soji、Ochiai Tomonori、Shirane Shuichi、Ando Jun、Komatsu Norio
  • Journal Title: Hematology Volume: 27 Issue: 1 Pages: 157-166
  • DOI: 10.1080/16078454.2021.2022848
• [Journal Article] Systemic chemotherapy combined with thrombopoietin receptor agonist for the treatment of diffuse large B-cell lymphoma complicated with aplastic anemia (2022)
  • Author(s): 福田 泰隆、枝廣 陽子、高久 智生、古屋 智帆、白根 脩一、浜埜 康晴、小池 道明、小松 則夫
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 1 Pages: 20-25
  • DOI: 10.11406/rinketsu.63.20
  • NAID: 130008158337
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Intravascular large B-cell lymphoma as a recurrence of primary central nervous system lymphoma after chemotherapy: A case report (2021)
  • Author(s): Edahiro Yoko、Takaku Tomoiku、Suzuki Mario、Fukuda Yasutaka、Harada Sakiko、Kinoshita Shintaro、Inano Tadaaki、Shirane Shuichi、Hamano Yasuharu、Kondo Akihide、Komatsu Norio
  • Journal Title: Leukemia Research Reports Volume: 15 Pages: 100249-100249
  • DOI: 10.1016/j.lrr.2021.100249
• [Journal Article] MPL overexpression induces a high level of mutant-CALR/MPL complex: a novel mechanism of ruxolitinib resistance in myeloproliferative neoplasms with CALR mutations (2021)
  • Author(s): Yasuda Shunichiro、Aoyama Satoru、Yoshimoto Ryoto、Li Huixin、Watanabe Daisuke、Akiyama Hiroki、Yamamoto Kouhei、Fujiwara Takeo、Najima Yuho、Doki Noriko、Sakaida Emiko、Edahiro Yoko、Imai Misa、Araki Marito、Komatsu Norio、Miura Osamu、Kawamata Norihiko
  • Journal Title: International Journal of Hematology Volume: 114 Issue: 4 Pages: 424-440
  • DOI: 10.1007/s12185-021-03180-0
  • Peer Reviewed
• [Journal Article] Long-term spontaneous regression of Stage IV diffuse large B-cell lymphoma (2021)
  • Author(s): Furukawa Yoshiki、Ando Jun、Ando Miki、Kinoshita Shintaro、Edahiro Yoko、Furuta Takuya、Ohshima Koichi、Komatsu Norio
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 61 Issue: 3 Pages: 168-172
  • DOI: 10.3960/jslrt.21002
  • NAID: 130008087357
  • ISSN: 1346-4280, 1880-9952
• [Journal Article] Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia (2021)
  • Author(s): Inano Tadaaki、Araki Marito、Morishita Soji、Imai Misa、Kihara Yoshihiko、Okuda Maho、Yang Yinjie、Ito Masafumi、Osaga Satoshi、Mano Hiroyuki、Edahiro Yoko、Ochiai Tomonori、Misawa Kyohei、Fukuda Yasutaka、Ando Jun、Komatsu Norio
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 17702-17702
  • DOI: 10.1038/s41598-021-97106-9
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study (2021)
  • Author(s): Hashimoto Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito TI, Kada A, Saito AM, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Edahiro Y, Akashi K, Matsumura I, Takenaka K, Komatsu N
  • Journal Title: International Journal of Hematology Volume: 115 Issue: 2 Pages: 208-221
  • DOI: 10.1007/s12185-021-03253-0
  • Peer Reviewed / Open Access
• [Journal Article] Clinical impacts of the mutational spectrum in Japanese patients with primary myelofibrosis (2021)
  • Author(s): Morishita Soji、Ochiai Tomonori、Misawa Kyohei、Osaga Satoshi、Inano Tadaaki、Fukuda Yasutaka、Edahiro Yoko、Ohsaka Akimichi、Araki Marito、Komatsu Norio
  • Journal Title: International Journal of Hematology Volume: 113 Issue: 4 Pages: 500-507
  • DOI: 10.1007/s12185-020-03054-x
  • Peer Reviewed
• [Journal Article] Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin (2020)
  • Author(s): Edahiro Yoko、Araki Marito、Komatsu Norio
  • Journal Title: Cancer Science Volume: 111 Issue: 8 Pages: 2682-2688
  • DOI: 10.1111/cas.14503
  • Peer Reviewed / Open Access
• [Journal Article] Interferon therapy for pregnant patients with essential thrombocythemia in Japan (2020)
  • Author(s): Edahiro Yoko、Yasuda Hajime、Gotoh Akihiko、Morishita Soji、Suzuki Toshifumi、Takeda Jun、Ando Jun、Tsutsui Miyuki、Itakura Atsuo、Komatsu Norio
  • Journal Title: International Journal of Hematology Volume: 113 Issue: 1 Pages: 106-111
  • DOI: 10.1007/s12185-020-03001-w
  • Peer Reviewed
• [Journal Article] Difficulty Diagnosing a Brain Tumor during Clinical Maintenance of a Complete Response to anti-HER2 Treatments for Metastatic Breast Cancer: A Case Report (2020)
  • Author(s): Ryoko Semba, Yoshiya Horimoto, Atsushi Arakawa, Yoko Edahiro, Tomoiku Takaku, Kotaro Iijima, Mitsue Saito
  • Journal Title: Case Reports in Oncology Volume: Sep-Dec;13(3) Issue: 3 Pages: 1311-1316
  • DOI: 10.1159/000511051
  • Peer Reviewed
• [Journal Article] CREB3L1 overexpression as a potential diagnostic marker of Philadelphia chromosome?negative myeloproliferative neoplasms (2020)
  • Author(s): Morishita Soji、Yasuda Hajime、Yamawaki Saya、Kawaji Hideya、Itoh Masayoshi、Edahiro Yoko、Imai Misa、Kogo Yasushi、Tsuneda Satoshi、Ohsaka Akimichi、Hayashizaki Yoshihide、Ito Masafumi、Araki Marito、Komatsu Norio
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 884-892
  • DOI: 10.1111/cas.14763
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in polycythemia vera treatment (2020)
  • Author(s): 枝廣 陽子
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 9 Pages: 1187-1194
  • DOI: 10.11406/rinketsu.61.1187
  • NAID: 130007937077
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface (2019)
  • Author(s): Masubuchi Nami、Araki Marito、Yang Yinjie、Hayashi Erina、Imai Misa、Edahiro Yoko、Hironaka Yumi、Mizukami Yoshihisa、Kihara Yoshihiko、Takei Hiraku、Nudejima Mai、Koike Masato、Ohsaka Akimichi、Komatsu Norio
  • Journal Title: Leukemia Volume: 34 Issue: 2 Pages: 499-509
  • DOI: 10.1038/s41375-019-0564-z
  • Peer Reviewed
• [Journal Article] JAK2 exon 12 mutation in myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Not an exclusive mutation to polycythaemia vera (2019)
  • Author(s): Inano, T. Araki, M. Morishita, S. Imai, M. Yasuda, H. Nitta, H. Ito, M. Edahiro, Y. Ochiai, T. Misawa, K. Fukuda, Y. Ohsaka, A. Komatsu, N.
  • Journal Title: British Journal of Haematology Volume: 187 Issue: 1
  • DOI: 10.1111/bjh.16146
  • Peer Reviewed
• [Journal Article] Efficacy and safety of ruxolitinib in patients with myelofibrosis: a single-center retrospective analysis (2019)
  • Author(s): 枝廣 陽子、小松 則夫
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 7 Pages: 755-760
  • DOI: 10.11406/rinketsu.60.755
  • NAID: 130007688020
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Specific mechanisms of subarachnoid hemorrhage accompanied by ischemic stroke in essential thrombocythemia: two case reports and a literature review (2019)
  • Author(s): Sugiyama Mizuho、Ueno Yuji、Kamo Hikaru、Edahiro Yoko、Miyamoto Nobukazu、Yamashiro Kazuo、Tanaka Ryota、Shimo Yasushi、Komatsu Norio、Hattori Nobutaka
  • Journal Title: Journal of Neurology Volume: 266 Issue: 8 Pages: 1869-1878
  • DOI: 10.1007/s00415-019-09347-4
• [Journal Article] Clinical and molecular features of patients with prefibrotic primary myelofibrosis previously diagnosed as having essential thrombocythemia in Japan (2019)
  • Author(s): Edahiro Yoko、Araki Marito、Inano Tadaaki、Ito Masafumi、Morishita Soji、Misawa Kyohei、Fukuda Yasutaka、Imai Misa、Ohsaka Akimichi、Komatsu Norio
  • Journal Title: European Journal of Haematology Volume: 00 Issue: 6 Pages: 1-5
  • DOI: 10.1111/ejh.13236
  • Peer Reviewed
• [Journal Article] Evidence for prevention of renal dysfunction associated with primary myelofibrosis by cytoreductive therapy (2019)
  • Author(s): Fukuda Yasutaka、Araki Marito、Yamamoto Kouji、Morishita Soji、Inano Tadaaki、Misawa Kyohei、Ochiai Tomonori、Edahiro Yoko、Imai Misa、Yasuda Hajime、Gotoh Akihiko、Ohsaka Akimichi、Komatsu Norio
  • Journal Title: Haematologica Volume: 印刷中 Issue: 11 Pages: e506-e509
  • DOI: 10.3324/haematol.2018.208876
  • Peer Reviewed / Open Access
• [Presentation] Specific expression of CREB3L1 in megakaryocyte in myeloproliferative neoplasms (2021)
  • Author(s): 奥田 真帆, 荒木 真理人, Federico Demarchi, 森下 総司, 今井 美沙, 森 洋輔, 堀野 芽生, 落合 友則, 白根 脩一, 枝廣 陽子, 安藤 純, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Quantitative measurement of mutant calreticulin in specimens of myeloproliferative neoplasm patients (2021)
  • Author(s): 尾形 智子, 荒木 真理人, 木原 慶彦, 奥田 真帆, 森下 総司, 今井 美沙, 増渕 菜弥, 森 洋輔, Yinjie Yang, 吉川 隼平, 落合 友則, 白根 脩一, 枝廣 陽子, 安藤 純, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Clinical presentation of thrombocytosis: A single-center retrospective study of 1202 patients (2021)
  • Author(s): 枝廣 陽子, 黒川 安満, 森下 総司, 荒木 真理人, 安藤 純, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Clinical characteristics of Japanese patients with polycythemia vera: JSH MPN-R18 study results (2021)
  • Author(s): 枝廣 陽子, 橋本 由徳, 伊藤 量基, 後藤 明彦, 中前 美佳, 木村 文彦, 小池 道明, 桐戸 敬太, 和田 秀穂, 臼杵 憲祐, 田中 孝幸, 森 毅彦, 脇田 知志, 齋藤 俊樹, 嘉田 晃子, 齋藤 明子, 下田 和哉, 杉本 由香, 黒川 敏郎, 冨田 章裕, 赤司 浩一, 松村 到, 竹中 克斗, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] A nationwide survey on Japanese patients with essential thrombocythemia: JSH-MPN-R18 study (2021)
  • Author(s): 橋本 由徳, 枝廣 陽子, 伊藤 量基, 後藤 明彦, 中前 美佳, 木村 文彦, 小池 道明, 桐戸 敬太, 和田 秀穂, 臼杵 憲祐, 田中 孝幸, 森 毅彦, 脇田 知志, 齋藤 俊樹, 嘉田 晃子, 齋藤 明子, 下田 和哉, 杉本 由香, 黒川 敏郎, 冨田 章裕, 赤司 浩一, 松村 到, 竹中 克斗, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Distributions of typical non-driver mutations in essential thrombocythemia and polycythemia vera (2021)
  • Author(s): 森下 総司、枝廣 陽子、橋本 由徳、白根 脩一、落合 友則、三澤 恭平、稲野 資明、福田 泰隆、森 洋輔、古屋 智帆、荒木 真理人、安藤 純、小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Absence of JAK2 mutation excludes polycythemia vera (2021)
  • Author(s): 森 洋輔, 荒木 真理人, 森下 総司, 今井 美沙, 枝廣 陽子, 伊藤 雅文, 落合 友則, 白根 脩一, 橋本 由徳, 安藤 純, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Diversity of thrombosis event-free survival by the treatment in essential thrombocythemia patients (2021)
  • Author(s): 馬場 照美, 橋本 由徳, 荒木 真理人, 安田 肇, 枝廣 陽子, 森下 総司, 落合 友則, 白根 脩一, 安藤 純, 小松 則夫
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] 第82回日本血液学会学術集会 (2020)
  • Author(s): Yoko Edahiro, Tomoiku Takaku, Yasutaka Fukuda, Sakiko Harada, Shintaro Kinoshita, Tadaaki Inano, Shuichi Shirane, Yasuharu Hamano, Norio Komatsu
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Two cases of R-CHOP therapy combined with eltrombopag for treatment DLBCL complicated with AA (2020)
  • Author(s): Yasutaka Fukuda, Tomoiku Takaku, Chiho Furuya, Shuichi Shiran, Yoko Edahiro, Yasuharu Hamano, Norio Komatsu
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Overexpression of MPL causes ruxolitinib-resistance in MPN with CALR frame-shift mutations (2020)
  • Author(s): Shunichiro Yasuda，Satoru Aoyama，Ryoto Yoshimoto，Daisuke Watanabe，Kouhei Yamamoto，Takeo Fujiwara，Yoko Edahiro， Misa Imai，Marito Araki，Norio Komatsu，Osamu Miura，Norihiko Kawamata
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] CREB3L1 overexpression as a novel diagnostic marker of myeloproliferative neoplasms (2020)
  • Author(s): Soji Morishita，Hajime Yasuda，Saya Yamawaki，Hideya Kawaji， Masayoshi Itoh，Yoko Edahiro，Misa Imai，Yasushi Kogo，Satoshi Tsuneda，Akimichi Ohsaka，Yoshihide Hayashizaki，Marito Araki，Norio Komatsu
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] MPL overexpression induces a high level of mutant-Calr/MPL complex: A novel mechanism of ruxolitinib resistance in myeloproliferative neoplasms with Calr mutations. (2020)
  • Author(s): Shunichiro Yasuda, Satoru Aoyama, Ryoto Yoshimoto, Daisuke Watanabe, Hiroki Akiyama, Kouhei Yamamoto, Takeo Fujiwara, Emiko Sakaida, Yoko Edahiro, Misa Imai, Marito Araki, Norio Komatsu, Norihiko Kawamata.
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] PV治療の最前線 (2020)
  • Author(s): 枝廣陽子
  • Organizer: 第82回日本血液学会学術集会
  • Invited
• [Presentation] Characteristics of juvenile essential thrombocythemia (2019)
  • Author(s): 枝廣陽子、森下総司、稲野資明、福田泰隆、黒川安満、森洋輔、大坂顯通、荒木真理人、小松則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Polycythemia vera complicated with paraneoplastic vasculitis (2019)
  • Author(s): 福田泰隆、枝廣陽子、森下総司、筒井深雪、新田英昭、安藤純、荒木真理人、小松則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] MPL高発現がCALR変異陽性骨髄増殖性疾患におけるロキソリチニブ耐性のメカニズムである。 (2019)
  • Author(s): 安田峻一郎、青山慧、吉本龍人、渡邉大介、山本浩平、枝廣陽子、荒木真理人、小松則夫、三浦修、川俣紀彦
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] The frequency of JAK2 V617F mutation in patients with myocardial or cerebral infarction (2019)
  • Author(s): 筒井深雪、森下総司、西野隆、枝廣陽子、常田聡、荒木真理人、大坂顯通、小松則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 真性トリプルネガティブ本態性血小板血症における臨床的・分子生物学的特異性 (2019)
  • Author(s): 稲野資明、荒木真理人、森下総司、落合友則、三澤恭平、福田泰隆、緑川直子、橳島麻衣、伊藤雅文、大佐賀智、枝廣陽子、今井美沙、田口鉄平、奥田真帆、大坂顯通、小松則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 変異型CALRはMPLと分泌経路で相互作用し細胞表面で活性化を引き起こす (2019)
  • Author(s): 増渕 菜弥, 荒木 真理人, 楊 印杰, 林 英里奈, 今井 美沙, 枝廣 陽子, 弘中 由美, 水上 喜久, 木原 慶彦, 小池 正人, 大坂 顯通, 小松 則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Correction of JAK2 V617F mutation in PV-derived iPSCs (2019)
  • Author(s): 枝廣陽子、劉暢、荒木真理人、橳島麻衣、森下総司、今井美沙、増渕菜弥、水上喜久、眞野修一、竹井拓、大坂顯通、小松則夫
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] The impact of allelic burden of JAK2V617F on human hematopoietic cell differentiation. (2019)
  • Author(s): 枝廣 陽子, 竹井 拓, Liu Chang, 橳島 麻衣, 森下 総司, 大坂 顯通, 荒木 真理人, 小松 則夫
  • Organizer: 第29回日本サイトメトリー学会学術集会
• [Presentation] 分泌経路における変異型分子シャペロンとサイトカイン受容体の会合による細胞の腫瘍化 (2019)
  • Author(s): 増渕 菜弥, 荒木 真理人, 木原 慶彦, 楊 印杰, 今井 美沙, 水上 喜久, 林 英里奈, 弘中 由美, 竹井 拓, 枝廣 陽子, 大坂 顯通, 小松 則夫
  • Organizer: 第29回日本サイトメトリー学会学術集会
• [Book] 未来型血液治療学 (2019)
  • Author(s): 小松則夫(編) 枝廣陽子他
  • Total Pages: 285
  • Publisher: 中外医学社
  • ISBN: 9784498225183