What is the true pathophysiology of PNH?: comprehensive analyses of gene and establishment of iPS cells from PNH patients

• Project/Area Number: 16K09854
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fukushima Medical University
• Principal Investigator: Noji Hideyoshi 福島県立医科大学, 医学部, 准教授 (20347214)
• Co-Investigator(Kenkyū-buntansha): 七島 勉 福島県立医科大学, 医学部, 博士研究員 (10192105)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PNH / iPS / ＰＮＨ / iPS細胞 / 遺伝子解析 / DNA解析 / 臨床

Outline of Final Research Achievements

We are now investigating comprehensive analyses of gene and establishing of iPS cells from PNH patients. Our iPS cells from PNH patients analyzed in this investigation have some characters of original cell lineage. We must establish perfect iPS cells, because we think that the pathophysiology of PNH is associated with all cell lineage.

Academic Significance and Societal Importance of the Research Achievements

我々は、これまでの研究と東北6県および北海道地区のPNH症例(登録50例)を対象とした凝固異常、造血状態異常および自己免疫異常の病態調査を行っており、PNHでこれまで考えられていた溶血以外の因子による血栓発症機序、PNHクローンの拡大には、腫瘍性増殖や免疫学的な攻撃を回避する機序、免疫学的異常や造血障害による血球減少が複雑に絡み合っている知見を得た。本研究では、すでに臨床病態が明らかなPNH症例を対象として、網羅的遺伝子解析を行いPNHの遺伝子異常を明らかにするとともに、種々の病態を示すPNH症例由来のiPS細胞を作成し、PNH病態モデルを作成することを目的に開始された。

Research Products

• [Journal Article] Mechanisms of Impaired Neutrophil Migration by MicroRNAs in Myelodysplastic Syndromes. (2017)
  • Author(s): Cao M, Shikama Y, Kimura H, Noji H, Ikeda K, Ono T, Ogawa K, Takeishi Y, Kimura J
  • Journal Title: J.Immunol. Volume: 198(5) Issue: 5 Pages: 1887-1899
  • DOI: 10.4049/jimmunol.1600622
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum. (2017)
  • Author(s): Yokoyama H, Takahashi N, Katsuoka Y, Inomata M, Ito T, Meguro K, Kameoka Y, Tsumanuma R, Murai K, Noji H, Ishizawa K, Ito S, Onishi Y, Harigae H; Tohoku Hematology Forum.
  • Journal Title: International Journal of Hematology Volume: 105(5) Issue: 5 Pages: 606-613
  • DOI: 10.1007/s12185-017-2190-8
  • Peer Reviewed
• [Journal Article] Establishment of induced pluripotent stem cells from normal B cells and inducing AID expression in their differentiation into hematopoietic progenitor cells (2017)
  • Author(s): Fumihiko Kawamura, Makoto Inaki, Atsushi Katafuchi, Yu Abe, Naohiro Tsuyama, Yumiko Kurosu, Aki Yanagi, Mitsunori Higuchi, Satoshi Muto, Takumi Yamaura, Hiroyuki Suzuki, Hideyoshi Noji, Shinichi Suzuki, Mitsuaki A. Yoshida, Megumi Sasatani, Kenji Kamiya, Masafumi Onodera & Akira Sakai
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41598-017-01627-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 内分泌療法と分子標的治療薬との併用 (2017)
  • Author(s): 佐治重衡、木村礼子、佐々木栄作、野地秀義
  • Journal Title: 日本臨牀 Volume: 75 Pages: 326-331
• [Journal Article] Clinicopathological characteristics of malignant lymphoma in patients with hepatitis C virus infection in the Tohoku district in Eastern Japan． (2016)
  • Author(s): Tajima K，Takahasi N，Ishizawa K，Murai K，Akagi T Noji H，Sasaki O，Wano M，Itoh J，Katou Y，Shichishima T，Harigae H，Ishida Y，Tohoku hematology forum
  • Journal Title: Leuk Lymphoma Volume: 10 Issue: 6 Pages: 1-3
  • DOI: 10.1080/10428194.2016.1236376
  • Peer Reviewed
• [Journal Article] High prevalence of diffuse large B-cell lymphoma in occult hepatitis B virus-infected patients in the Tohoku district in Eastern Japan． (2016)
  • Author(s): Tajima K，Takahasi N，Ishizawa K，Murai K，Akagi T Noji H，Sasaki O，Wano M，Itoh J，Kato Y， Shichishima T，Ishida Y，Harigae H，Sawada K，Tohoku Hematology Forum
  • Journal Title: J Med Virol． Volume: 88 Issue: 12 Pages: 2206-2210
  • DOI: 10.1002/jmv.24584
  • Peer Reviewed / Open Access
• [Journal Article] Causes of macrocytic anemia among 628 patients: mean corpuscular volumes of 114 and 130 fL as critical markers for categorization (2016)
  • Author(s): Natsuko Takahashi, Junichi Kameoka, Naoto Takahashi, Yoshiko Tamai, Kazunori Murai, Riko Honma, Hideyoshi Noji, Hisayuki Yokoyama, Yasuo Tomiya, Yuichi Kato, Kenichi Ishizawa, Shigeki Ito, Yoji Ishida, Kenichi Sawada, Hideo Harigae
  • Journal Title: International Journal of Hematology Volume: 10 (3) Issue: 3 Pages: 344-357
  • DOI: 10.1007/s12185-016-2043-x
  • Peer Reviewed
• [Journal Article] Analysis of chromosome translocation frequency after a single CT scan in adults (2016)
  • Author(s): Yu Abe, Tomisato Miura, Mitsuaki A. Yoshida, et al.
  • Journal Title: Journal of Radiation Research, Volume: 57 Issue: 3 Pages: 1-7
  • DOI: 10.1093/jrr/rrv090
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients. (2016)
  • Author(s): Shikama Y, Cao M, Ono T, Feng X, Noji H, Kimura H, Ogawa K, Suzuki Y, Ikeda K, Takeishi Y, Kimura J.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0158527-e0158527
  • DOI: 10.1371/journal.pone.0158527
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular response of e19a2 BCR-ABL1 chronic myeloid leukemia with double Philadelphia chromosome by dasatinib (2016)
  • Author(s): Ikeda K, Harada-Shirado K, Matsumoto H, Noji H, Ogawa K, Takeishi Y
  • Journal Title: Journal of Clinical Oncology Volume: 34 Issue: 14 Pages: e130-e133
  • DOI: 10.1200/jco.2013.51.1188
  • Peer Reviewed / Open Access
• [Presentation] The first follow-up data analysis of patients with acquired bone marrow failure harboring a small population of PNH-Type cells in the Japanese, Multicenter, Prospective Study Optima (2016)
  • Author(s): Yukari Shirasugi, Chiharu Sugimori, Hideyoshi Noji, Tsutomu Shichishima, Naoshi Obara, Shigeru Chiba, Haruhiko Ninomiya, Yoshihiko Nakamura, Kiyoshi Ando, Yuji Yonemura, Tatsuya Kawaguchi, Kohei Hosokawa, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Shinji Nakao.
  • Organizer: 58th American Society of Hematology (ASH) Annual Meeting and Exposition
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Relationship between thrombosis and coagulation markers in patients with PNH. (2016)
  • Author(s): H Noji, K Murai, J Kameoka, S Ito, O Yasushi, K Takada, S Saito, H Kimura, K Ikeda, K Yamaguchi, N Fujishima, H Yokoyama, H Kanbayashi, J Kato, N Takahashi, O Eijirou, K Ishizawa, Y Ishida, H Harigae, Y Takeishi, T Shichishima.
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Two-year consolidation by nilotinib might improve the TFR of STIM trial in CML with DMR. (2016)
  • Author(s): Kaichi Nishiwaki, Naoto Takahashi, Chiaki Nakaseko, Hisashi Wakita, Koji Sano, Chikako Ohwada, Nobuyuki Aotsuka, Jun Kuroki, Hideo Kimura, Hideyoshi Noji, Michihide Tokuhira, Kinuko Mitani, Kazuhisa Fujikawa, Osamu Iwase, Kohshi Ohishi, Fumihiko Kimura, Tetsuya Fukuda, Sakae Tanosaki, Masatomo Miura, Kenichi Sawada.
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] High sensitivity flow cytometry to detect small population of PNH clone in bone marrow failure syndrome in Japan. (2016)
  • Author(s): Yasutaka Ueda, Jun-ichi Nishimura, Chiharu Sugimori, Kohei Hosokawa, Yuji Yonemura, Naoshi Obara, Hideyoshi Noji, Yoshihiko Nakamura, Yukari Shirasugi, Kiyoshi Ando, Tsutomu Shichishima, Haruhiko Ninomiya, Shigeru Chiba, Tatsuya Kawaguchi, Yuzuru Kanakura, Shinji Nakao.
  • Organizer: 26th International Complement Workshop
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] A clinical significance and time-dependent change of PHN clone size in patients with bone marrow failure syndrome: Japanese Mmulti-centre prospective study. (2016)
  • Author(s): Yukari Shirasugi, Chiharu Sugimori, Hideyoshi Noji, Tsutomu Shichishima, Naoshi Obara, Shigeru Chiba, Haruhiko Ninomiya, Yoshihiko Nakamura, Kiyoshi Ando, Yuji Yonemura, Tatsuya Kawaguchi, Kohei Hosokawa, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Shinji Nakao.
  • Organizer: 21st Congress of European Hematology Association
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Book] Paroxysmal Nocturnal Hemoglobinuria From Bench to Bedside (2017)
  • Author(s): Shichishima Tsutomu, Noji Hideyoshi
  • Total Pages: 358
  • Publisher: Springer Japan
• [Book] 今日の治療指針 2017年版 (2017)
  • Author(s): 野地秀義
  • Total Pages: 1999
  • Publisher: 医学書院
• [Book] 血液科研修ノート (2016)
  • Author(s): 野地秀義, 七島 勉
  • Total Pages: 560
  • Publisher: 診断と治療社
• [Book] 発作性夜間ヘモグロビン尿症（PNH) 遺伝子異常の解析から新規治療の臨床・開発まで (2016)
  • Author(s): 野地秀義, 七島 勉
  • Total Pages: 239
  • Publisher: 医薬ジャーナル社