MPN research focusing on ER stress response and tumor-derived fibrocytes

• Project/Area Number: 20H03713
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Shimoda Kazuya 宮崎大学, 医学部, 教授 (90311844)
• Co-Investigator(Kenkyū-buntansha): 久冨木 庸子 宮崎大学, 医学部, 講師 (00284836) ; 幣 光太郎 宮崎大学, 医学部, 助教 (20468028) ; 亀田 拓郎 宮崎大学, 医学部, 助教 (30468029)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2020: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 骨髄増殖性腫瘍 / 小胞体ストレス / 骨髄線維症 / fibrocyte / シグナル伝達

Outline of Research at the Start

骨髄増殖性腫瘍(MPN)では、JAK2、CALR変異によるJAK-STATシグナル伝達経路活性化の機序が明確になってきた。一方、CALR変異造血幹細胞 (HSC) のクローン拡大メカニズム、および骨髄線維化のメカニズムに関しては未解明である。本研究では、以下のテーマについて病態解明と創薬につながる研究を行う。
テーマ1: CALR欠損により生じるERストレスが変異HSCに及ぼす影響の解明と、亢進したERストレスを標的とする治療開発
テーマ2: 腫瘍細胞がfibrocyteへ分化するメカニズムの解明と、単球-fibrocyteを標的とした、2次性骨髄線維症早期診断法および治療法の開発

Outline of Final Research Achievements

The cell proliferation mechanism of myeloproliferative neoplasms (MPN) is JAK-STAT signaling activation by JAK2 and CALR mutations. On the other hand, the characteristics of CALR-mutant hematopoietic stem cells (HSCs) and the mechanism of bone marrow fibrosis are unknown, and the mechanisms of bone marrow fibrosis remain to be elucidated.
Using the MPN mouse model, we revealed the gene expression profile of the ER stress pathway in CALR-mutant HSCs. We also clarified the effects of ER stress reduction by chemical chaperones on MPN pathology.We identified the surface antigens of neoplastic fibrocytes, the cells responsible for fibrosis, and their progenitor cells, the neoplastic monocytes. Compounds that inhibit the differentiation of monocytes to fibrocytes were identified using existing and novel compound libraries.

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかになったCALR欠損により生じるERストレス応答亢進とその制御に関する知見、そして骨髄線維化の責任細胞である単球由来の腫瘍性fibrocyteの同定と分化経路、治療標的化に関する知見は、MPNの病態、骨髄線維症の発症機構の解明に大きく貢献するものである。これらの成果は2次性骨髄線維症早期診断法や、現在の標準薬物療法であるJAK阻害剤では改善が乏しい骨髄線維化の新規治療法開発の端緒となることが期待できる。

Research Products

• [Journal Article] Immunohistopathological Analysis of Extramedullary Hematopoiesis and Angiogenesis of Spleen in a Case of Primary Myelofibrosis with Huge Splenomegaly (2022)
  • Author(s): Kawano N, Saito N, Yoshida S, Kitanaka A, Shide K, Marutsuka K, Ohshima K, Shimoda K
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 256 Issue: 2 Pages: 119-125
  • DOI: 10.1620/tjem.256.119
  • NAID: 130008160463
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Momelotinib reduces transfusion requirements in patients with myelofibrosis (2022)
  • Author(s): Mesa Ruben、Oh Stephen T.、Gerds Aaron T.、Gupta Vikas、Catalano John、Cervantes Francisco、Devos Timothy、Hus Marek、Kiladjian Jean-Jacques、Lech-Maranda Ewa、McLornan Donal、Palmer Jeanne、Platzbecker Uwe、Treli?ski Jacek、Shimoda Kazuya、Donahue Rafe、D’Hollander Koenraad、Kowalski Mark、Verstovsek Srdan
  • Journal Title: Leukemia & Lymphoma Volume: 63 Issue: 7 Pages: 1718-1722
  • DOI: 10.1080/10428194.2022.2043304
  • Peer Reviewed
• [Journal Article] Efficacy and safety of ropeginterferon alfa-2b in Japanese patients with polycythemia vera: an open-label, single-arm, phase 2 study. (2022)
  • Author(s): Edahiro Y, Ohishi K, Gotoh A, Takenaka K, Shibayama H, Shimizu T, Usuki K, Shimoda K, Ito M, VanWart SA, Zagrijtschuk O, Qin A, Kawase H, Miyachi N, Sato T, Komatsu N, Kirito K.
  • Journal Title: Int J Hematol Volume: ー Issue: 2 Pages: 215-227
  • DOI: 10.1007/s12185-022-03341-9
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of Japanese patients with polycythemia vera: results of the JSH-MPN-R18 study (2022)
  • Author(s): Edahiro Yoko、Tomita Akihiro、et al.
  • Journal Title: International Journal of Hematology Volume: 116 Issue: 5 Pages: 696-711
  • DOI: 10.1007/s12185-022-03412-x
  • Peer Reviewed / Open Access
• [Journal Article] New aspects of myeloproliferative neoplasms: COVID-19 and myeloproliferative neoplasms (2022)
  • Author(s): 幣 光太郎
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 6 Pages: 647-654
  • DOI: 10.11406/rinketsu.63.647
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis (2021)
  • Author(s): Shinoda Daisuke、Nakajima-Takagi Yaeko、Oshima Motohiko、Koide Shuhei、Aoyama Kazumasa、Saraya Atsunori、Harada Hironori、Rahmutulla Bahityar、Kaneda Atsushi、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Shimoda Kazuya、Tanaka Tomoaki、Sashida Goro、Iwama Atsushi
  • Journal Title: Leukemia Volume: 36 Issue: 2 Pages: 452-463
  • DOI: 10.1038/s41375-021-01402-2
  • Peer Reviewed / Open Access
• [Journal Article] Fibrocytes in primary myelofibrosis (2021)
  • Author(s): Kazuya Shimoda, Yoshinori Ozono, Kotaro Shide
  • Journal Title: Oncotarget Volume: 12 Issue: 20 Pages: 2101-2103
  • DOI: 10.18632/oncotarget.27971
  • Peer Reviewed / Open Access
• [Journal Article] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils (2021)
  • Author(s): Kimishima Yusuke、Misaka Tomofumi、Yokokawa Tetsuro、Wada Kento、Ueda Koki、Sugimoto Koichi、Minakawa Keiji、Nakazato Kazuhiko、Ishida Takafumi、Oshima Motohiko、Koide Shuhei、Shide Kotaro、Shimoda Kazuya、Iwama Atsushi、Ikeda Kazuhiko、Takeishi Yasuchika
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6177-6177
  • DOI: 10.1038/s41467-021-26435-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Circulating CD34+?cells of primary myelofibrosis patients contribute to myeloid-dominant hematopoiesis and bone marrow fibrosis in immunodeficient mice (2021)
  • Author(s): Saito Noriyuki、Yamauchi Takuji、Kawano Noriaki、Ono Rintaro、Yoshida Shuro、Miyamoto Toshihiro、Kamimura Tomohiko、Shultz Leonard D.、Saito Yoriko、Takenaka Katsuto、Shimoda Kazuya、Harada Mine、Akashi Koichi、Ishikawa Fumihiko
  • Journal Title: International Journal of Hematology Volume: 115 Issue: 2 Pages: 198-207
  • DOI: 10.1007/s12185-021-03239-y
  • Peer Reviewed / Open Access
• [Journal Article] JAK2-negative acute monocytic leukemia with TET2 mutation in essential thrombocythemia with JAK2 mutation with literature review (2020)
  • Author(s): Ogasawara Toshie、Kawauchi Kiyotaka、Ono Takuya、Marshall Shoko、Shide Kotaro、Shimoda Kazuya、Mori Naoki、Sakura Hiroshi
  • Journal Title: Leukemia Research Reports Volume: 13 Pages: 100194-100194
  • DOI: 10.1016/j.lrr.2019.100194
  • Peer Reviewed / Open Access
• [Journal Article] Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice (2020)
  • Author(s): Ozono Yoshinori、Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Tahira Yuki、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Iwakiri Hisayoshi、Sueta Mitsue、Hidaka Tomonori、Kubuki Yoko、Yamamoto Shojiro、Hasuike Satoru、Sawaguchi Akira、Nagata Kenji、Shimoda Kazuya
  • Journal Title: Leukemia Volume: - Issue: 2 Pages: 454-467
  • DOI: 10.1038/s41375-020-0880-3
  • Peer Reviewed / Open Access
• [Journal Article] Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms (2020)
  • Author(s): Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Ozono Yoshinori、Tahira Yuki、Yokomizo-Nakano Takako、Kubota Sho、Ono Masaya、Ikeda Kazuhiko、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Hidaka Tomonori、Kubuki Yoko、Iwakiri Hisayoshi、Hasuike Satoru、Nagata Kenji、Sashida Goro、Shimoda Kazuya
  • Journal Title: Blood Volume: - Pages: 106-118
  • DOI: 10.1182/blood.2019003358
  • Peer Reviewed / Open Access
• [Journal Article] Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers (2020)
  • Author(s): Fagnan A,Bagger FO, Piqué-Borràs MR, Ignacimouttou C, Caulier A, Lopez CK, Robert E, Uzan B, Gelsi-Boyer V, Aid Z, Thirant C, Moll U, Tauchmann S, Kurtovic-Kozaric A, Maciejewski J, Dierks C, Spinelli O, Salmoiraghi S, Pabst T, Shimoda K , Mercher T
  • Journal Title: Blood Volume: 136 Issue: 6 Pages: 698-714
  • DOI: 10.1182/blood.2019003062
  • Peer Reviewed
• [Journal Article] JSH Practical Guidelines for Hematological Malignancies, 2018: I. Leukemia-4. Chronic myeloid leukemia (CML)/myeloproliferative neoplasms (MPN) (2020)
  • Author(s): Shimoda Kazuya、Takahashi Naoto、Kirito Keita、Iriyama Noriyoshi、Kawaguchi Tatsuya、Kizaki Masahiro
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 3 Pages: 268-291
  • DOI: 10.1007/s12185-020-02964-0
  • Peer Reviewed / Open Access
• [Presentation] Safety and efficacy of ropeginterferon alfa-2b in Japanese polycythemia vera patients: Phase 2 study (2022)
  • Author(s): Edahiro Y,Ohishi K, Gotoh A, Takenaka K, Shibayama H, Shimizu T, Usuki K, Shimoda K, Ito M, Scott A. VanWart, Oleh Zagrijtschuk, Albert Qin, Kawase H, Miyachi N, Sato T, Komatsu N, Kirito K:
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] TYK2 is essential for inhibition of cell proliferation by IFNα (2022)
  • Author(s): Tahira Y, Shide K, Kameda T, Kamiunten A, Akizuki K, Hidaka T, Kubuki Y, Shimoda K:
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Hematopoietic cells with MPN driver mutations promote pulmonary hypertension (2021)
  • Author(s): Ikeda K, Misaka T, Kimishima Y, Yokokawa T, Minakawa K, Ueda K, Oshima M, Koide S, Shide K, Shimoda K, Nakajima O, Iwama A, Takeishi Y
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Loss of EZH2 does not affect the severity of murine myeloproliferative neoplasms with CALR mutation (2021)
  • Author(s): Kamiunten A, Tahira Yuki, Akizuki K, Sekine M, Kameda T, Shide K, Hidaka T, Kubuki Y, Shimoda K
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] PRC1.1 insufficiency promotes the development of myelofibrosis (2021)
  • Author(s): Shinoda D, Nakajima Y, Oshima M, Koide S, Aoyama K, Saraya A, Harada H, Koseki H, Shimoda K, Sashida G, Iwama A
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] RNA splicing machinery gene mutations in patients with myeloproliferative neoplasms (MPNs) in Japan (2021)
  • Author(s): Shide K, Ogawa S, Kamiunten A, Kubuki Y, Takeuchi M, Matsue K, Shimomura T, Suzushima H, Kawano N, Yamashita K, Yasumi M, Karasuno T, Imataki O, Kadowaki N, Yonezawa A, Otsuka E, Hidaka T, Kameda T, Akizuki K, Sekine M, Tahira Y, Shimoda K
  • 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): Edahiro K, 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 T, Kada A, Saito A, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Akashi K, Matsumura I, Takenaka K, Komatsu N
  • 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): Hashimoto Y, Edahiro Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito T, Kada A, Saito A, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Akashi K, Matsumura I, Takenaka K, Komatsu N
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Secondary malignancies in Japanese patients with myeloproliferative neoplasms: JSH-MPN-R18 study (2021)
  • Author(s): Ochiai T, Hashimoto Y, Edahiro Y, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito T, Kada A, Saito A, Shimoda K, Sugimoto Y, Kurokawa T, Tomita A, Akashi K, Matsumura I, Takenaka K, Komatsu N
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Renal impairment associated with myeloproliferative neoplasm (MPN) (2021)
  • Author(s): Tahira Y, Shide K, Kamiunten A, Kameda T, Akizuki K, Sekine M, Hidaka T, Kubuki Y, Shimoda K
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] JAK2V617F による炎症性サイトカインIL1αの産生亢進メカニズム (2020)
  • Author(s): 幣光太郎、上運天綾子、大園芳範、亀田拓郎、田平優貴、秋月渓一、関根雅明、日高智徳、久冨木庸子、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] 骨髄増殖性腫瘍におけるSRSF2，U2AF1，IDH 変異の頻度と予後への影響 (2020)
  • Author(s): 小川紗葵、幣光太郎、上運天綾子、久冨木庸子、竹内正美、末永孝生、下村泰三、鈴島仁、河野徳明、山下清、安見正人、烏野隆博、今滝修、門脇則光、米澤昭仁、大塚英一、日高智徳、亀田拓郎、秋月渓一、関根雅明、田平優貴、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] CALR 変異を伴った5 番染色体長腕欠失の骨髄異形成症候群の1 例 (2020)
  • Author(s): 藤原志保、幣光太郎、下田和哉、有馬信之、木村由紀子、渡邊祐子、下村泰三、鈴島仁
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] マウスモデルにおいてJak2V617F 変異によって誘導される骨髄増殖性腫瘍に伴う腎障害 (2020)
  • Author(s): 田平優貴、幣光太郎、大園芳範、上運天綾子、亀田拓郎、秋月渓一、関根雅明、日高智徳、久冨木庸子、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Book] 今日の治療指針 2023年版［デスク判］ (2023)
  • Author(s): 福井 次矢、高木 誠、小室 一成
  • Total Pages: 2192
  • Publisher: 医学書院
  • ISBN: 9784260050357
• [Book] 内科学 第12版［原発性骨髄線維症］ (2022)
  • Author(s): 下田和哉
  • Total Pages: 2572
  • Publisher: 朝倉書店
  • ISBN: 9784254322804
• [Book] 専門医のための血液病学［白血球系疾患 原発性骨髄線維症］ (2022)
  • Author(s): 田平優貴、下田和哉
  • Total Pages: 432
  • Publisher: 医学書院
  • ISBN: 9784260047722
• [Book] 造血器腫瘍診療ガイドライン 2018年版補訂版［2020年4月］ [慢性骨髄性白血病・骨髄増殖性腫瘍（CML/MPN)] (2020)
  • Author(s): 下田和哉、入山規良、川口辰哉、木崎昌弘、桐戸敬太、髙橋直人
  • Total Pages: 428
  • Publisher: 金原出版
  • ISBN: 9784307102018
• [Book] Hematopaseo [骨髄増殖性腫瘍の分子病態研究の進歩 ドライバー変異とエピゲノム異常の関わり] (2020)
  • Author(s): 下田和哉：
  • Total Pages: 72
  • Publisher: 凸版印刷株式会社
  • ISBN: 9784909633132
• [Book] EBM 血液疾患の治療 2021-2022 [原発性骨髄線維症（PMF)の治療] (2020)
  • Author(s): 上運天綾子、下田和哉
  • Total Pages: 637
  • Publisher: 中外医学社
  • ISBN: 9784498225244