Novel therapeutic approaches for treatment of myeloproliferative neoplasms based on aging control

• Project/Area Number: 18K08358
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Yujiri Toshiaki 山口大学, 大学院医学系研究科, 教授 (80346551)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨髄増殖性腫瘍 / 細胞老化

Outline of Final Research Achievements

Myeloproliferative neoplasms (MPN) are often characterized by specific somatic mutations: JAK2, CALR, or MPL. A single nucleotide polymorphism (SNP), rs2736100, in the reverse transcriptase gene (TERT) and a germline JAK2 46/1 haplotype(46/1) have been associated with MPN in North American and European patients. We examined 201 Japanese MPN patients, as well as 366 control individuals for TERT rs2736100 and JAK2 rs10974944, a tagging SNP of the 46/1. Correlations between the JAK2 V617F allele burden and TERT rs2736100 or JAK2 rs10974944 were evaluated using a digital PCR assay. The 46/1, but not the TERT rs2736100, was correlated to the JAK2 V617F mutant allele burden in JAK2 V617F-positive MPN patients. In conclusion, we demonstrated that both TERT rs2736100_C and 46/1 are predisposing factors for MPNs in Japanese patients. While TERT rs2736100_C tended to have a more general, non-specific effect on all MPNs, the 46/1 was essentially predisposed to the JAK2 V617F-positive MPNs.

Academic Significance and Societal Importance of the Research Achievements

骨髄増殖性腫瘍は高齢者によく認められる疾患である。一般的には経過の緩徐な疾患であるが、脳心血管疾患リスクは高くなり生活の質が低下する。さらに二次性骨髄線維症や急性骨髄性白血病への病勢進行に加え、他の固形癌の発症も問題になる。今回の我々の研究では遺伝的背景(TERT遺伝子多型）に起因する骨髄増殖性腫瘍に加え、他の固形癌のリスク因子となるが日本人患者でも明らかになった。今後、高齢患者の増加に伴い重複癌患者の増加が推測されていることから重要な情報となる事が考えられる。また血管リスク因子を遺伝的背景から同定することができれば、さらに有用な情報となり得る。

Research Products

• [Journal Article] Differentiation of pulmonary complications with extensive ground-glass attenuation on high-resolution CT in immunocompromised patients (2021)
  • Author(s): Kunihiro Yoshie、Tanaka Nobuyuki、Kawano Reo、Matsumoto Tsuneo、Kobayashi Taiga、Yujiri Toshiaki、Kubo Makoto、Gondo Toshikazu、Ito Katsuyoshi
  • Journal Title: Japanese Journal of Radiology Volume: in press Issue: 9 Pages: 868-876
  • DOI: 10.1007/s11604-021-01122-8
  • NAID: 210000177793
  • ISSN: 1867-1071, 1867-108X
  • Peer Reviewed
• [Journal Article] Chest complications in immunocompromised patients without acquired immunodeficiency syndrome (AIDS): differentiation between infectious and non-infectious diseases using high-resolution CT findings (2021)
  • Author(s): N Tanaka, Y Kunihiro, R Kawano, T Yujiri, K Ueda, T Gondo, T Matsumoto
  • Journal Title: Clin Radiol . Volume: 76 Pages: 50-59
  • DOI: 10.1016/j.crad.2020.07.029
  • Peer Reviewed
• [Journal Article] Soluble Interleukin-2 Receptor Index Predicts Outcomes After Cord Blood Transplantation (2021)
  • Author(s): Kajimura Y, Nakamura Y, Tanaka Y, Tanaka M, Yamamoto K, Matsuguma M, Tokunaga Y, Yujiri T, Tanizawa Y.
  • Journal Title: Transplantation Proceedings Volume: 53 Pages: 379-385
  • DOI: 10.1016/j.transproceed.2020.03.027
  • Peer Reviewed / Open Access
• [Journal Article] Optimal treatment strategy with nilotinib for patients with newly diagnosed chronic-phase chronic myeloid leukemia based on early achievement of deep molecular response (MR 4.5 ): The phase 2, multicenter N-Road study (2020)
  • Author(s): Kaichi Nishiwaki, Kei-Ji Sugimoto, Shigehisa Tamaki, Junichi Hisatake, Hisayuki Yokoyama, Tadahiko Igarashi, Atsushi Shinagawa, Takeaki Sugawara, Satoru Hara, Kazuhisa Fujikawa, Seiichi Shimizu, Toshiaki Yujiri, Arinobu Tojo, Hisashi Wakita
  • Journal Title: Cancer Med . Volume: 9 Pages: 3742-3751
  • DOI: 10.1002/cam4.3034
  • Peer Reviewed / Open Access
• [Journal Article] TERT and JAK2 polymorphisms define genetic predisposition to myeloproliferative neoplasms in Japanese patients. (2019)
  • Author(s): Matsuguma M, Yujiri T, Yamamoto K, Kajimura Y, Tokunaga Y, Tanaka M, Tanaka Y, Nakamura Y, Tanizawa Y.
  • Journal Title: Int J Hematol. Volume: 110 Pages: 690-698
  • DOI: 10.1007/s12185-019-02742-7
  • Peer Reviewed
• [Journal Article] A Case of Pulmonary Langerhans Cell Histiocytosis With Acute Progressive Nodular Lesions Depicted on High-Resolution Computed Tomography. (2019)
  • Author(s): Kunihiro Y, Hara A,, Ikeda E, Nakada N, Murakami T, Hayashi M, Okabe K, Yujiri T, Kamei H, Tanaka N, Onoda H, Matsumoto T, Ito K
  • Journal Title: J Thorac Imaging. Volume: 34
  • DOI: 10.1097/rti.0000000000000446
  • Peer Reviewed
• [Journal Article] Differential diagnosis of pulmonary infections in immunocompromised patients using high-resolution computed tomography. (2019)
  • Author(s): Kunihiro Y, Tanaka N,, Kawano R, Yujiri T, Kubo M, Ueda K, Gondo T, Kobayashi T, Matsumoto T.
  • Journal Title: Eur Radiol. Volume: 29 Pages: 6089-6099
  • DOI: 10.1007/s00330-019-06235-3
  • Peer Reviewed
• [Journal Article] Significance of Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine, Cyclophosphamide, and Total Body Irradiation in Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignant Neoplasms. (2019)
  • Author(s): Nakamura Y, Tanaka Y, Tanaka M, Yamamoto K, Matsuguma M, Kajimura Y, Tokunaga Y, Yujiri T, Tanizawa Y
  • Journal Title: Transplant Proc. Volume: 51 Pages: 896-900
  • DOI: 10.1016/j.transproceed.2019.01.079
  • Peer Reviewed
• [Journal Article] Bortezomib-based strategy with autologous stem cell transplantation for newly diagnosed multiple myeloma: a phase II study by the Japan Study Group for Cell Therapy and Transplantation (JSCT-MM12). (2019)
  • Author(s): Sunami K, Matsumoto M, Fuchida SI, Omoto E, Takamatsu H, Adachi Y, Choi I, Fujishima N, Kiguchi T, Miyamoto T, Maeda A, Suzumiya J, Yamamura R, Nagafuji K, Nakazato T, Kuroda Y, Yujiri T, Takamatsu Y, Harada M, Akashi K
  • Journal Title: Int J Clin Oncol. Volume: 24 Pages: 966-975
  • DOI: 10.1007/s10147-019-01436-8
  • Peer Reviewed
• [Journal Article] Transient Appearance of Plasmablasts in the Peripheral Blood of Japanese Patients With Severe Fever With Thrombocytopenia Syndrome. (2019)
  • Author(s): Takahashi T, Suzuki T, Hiroshige S, Nouno S, Matsumura T, Tominaga T, Yujiri T, Katano H, Sato Y, Hasegawa H.
  • Journal Title: J Infect Dis. Volume: 220 Pages: 23-27
  • DOI: 10.1093/infdis/jiz054
  • Peer Reviewed
• [Journal Article] Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL (2018)
  • Author(s): Hatta Y, Mizuta S, Matsuo K, Ohtake S, Iwanaga M, Sugiura I, Doki N, Kanamori H, Ueda Y, Yoshida C, Dobashi N, Maeda T, Yujiri T, Monma F, Ito Y, Hayakawa F, Takeuchi J, Kiyoi H, Miyazaki Y, Naoe T
  • Journal Title: Ann Hematol. Volume: 97 Pages: 1535-1545
  • DOI: 10.1007/s00277-018-3323-8
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: A Nationwide Survey in Japan (2018)
  • Author(s): Kawajiri-Manako Chika、Sakaida Emiko、Ohwada Chikako、Miyamoto Toshihiro、Azuma Taichi、Taguchi Jun、Mori Takehiko、Hasegawa Yuichi、Kondo Tadakazu、Yujiri Toshiaki、Yoshimitsu Makoto、Imada Kazunori、Kurahashi Shingo、Kahata Kaoru、Ichinohe Tatsuo、Hirokawa Makoto、Atsuta Yoshiko、Nakaseko Chiaki
  • Journal Title: Biol Blood Marrow Transplant Volume: 24 Pages: 1180-1186
  • DOI: 10.1016/j.bbmt.2018.01.026
  • Peer Reviewed
• [Journal Article] A distinct subtype of Epstein Barr virus positive T/NK-cell lymphoproliferative disorder: Adult patients with chronic active Epstein Barr virus infection-like features. (2018)
  • Author(s): Kawamoto K, Miyoshi H, Suzuki T, Kozai Y, Kato K, Miyahara M, Yujiri T, Choi I, Fujimaki K, Muta T, Kume M, Moriguchi S, Tamura S, Kato T, Tagawa H, Makiyama J, Kanisawa Y, Sasaki Y, Kurita D, Yamada K, Shimono J, Sone H, Takizawa J, Seto M, Kimura H, Ohshima K.
  • Journal Title: Haematologica Volume: Epub Pages: 1018-1028
  • DOI: 10.3324/haematol.2017.174177
  • Peer Reviewed / Open Access
• [Journal Article] High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG (2018)
  • Author(s): Sakura T、Hayakawa F、Sugiura I、Murayama T、Imai K、Usui N、Fujisawa S、Yamauchi T、Yujiri T、Kakihana K、Ito Y、Kanamori H、Ueda Y、Miyata Y、Kurokawa M、Asou N、Ohnishi K、Ohtake S、Kobayashi Y、Matsuo K、Kiyoi H、Miyazaki Y、Naoe T
  • Journal Title: Leukemia. Volume: 32 Pages: 626-632
  • DOI: 10.1038/leu.2017.283
  • Peer Reviewed / Open Access
• [Presentation] 著明な甲状腺腫大をきたしたT細胞性前リンパ球白血病の一例 (2021)
  • Author(s): 藤岡 侑香，山本 薫，中邑 幸伸，徳永 良洋，松隈 雅史，竹田 孔明，湯尻 俊昭，谷澤 幸生
  • Organizer: 第60回日本血液学会中国四国地方会
• [Presentation] 同種移植後にレナリドミドによる尿細管間質性腎炎を合併した成人T細胞白血病リンパ腫 (2021)
  • Author(s): 中邑幸伸，佐々木貴宏，德永良洋，梶邑泰子，松隈雅史，山本 薫，上杉憲子，湯尻俊昭，谷澤幸生
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] MECOM遺伝子多型は日本人骨髄増殖性腫瘍発症の遺伝的素因とならない (2020)
  • Author(s): 松隈 雅史, 湯尻 俊昭, 梶邑 泰子, 徳永 良洋, 山本 薫, 佐々木 貴宏, 田中 真由美, 田中 芳紀, 中邑 幸伸, 谷澤 幸生
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] CD34 E-Scoreは自家末梢血幹細胞採取成否の予測モデルとなる (2020)
  • Author(s): 山本 薫, 中邑 幸伸, 重本 航輝, 田中 芳紀, 田中 真由美, 佐々木 貴宏, 徳永 良洋, 梶邑 泰子, 松隈 雅史, 湯尻 俊昭, 谷澤 幸生
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 未治療多発性骨髄腫に対する自家造血幹細胞移植の第2相試験（JSCT-MM14） (2020)
  • Author(s): 角南 一貴, 長藤 宏司, 上村 智彦, 宮本 敏浩, 松本 守生, 小川 亮介, 村田 了一, 瀧澤 淳, 松村 到, 大本 英次郎, 半田 寛, 湯尻 俊昭, 富永 亮, 高松 博幸, 日高 道弘, 杉田 純一, 藤島 直仁, 淵田 真一, 高松 泰, 原田 実根, 赤司 浩一
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 遺伝子チップによるMPN疾患関連遺伝子変異の検出 (2019)
  • Author(s): 吉村翠, 高光恵美, 大場光芳, 山野博文, 松隈雅史, 湯尻俊昭
  • Organizer: 第59回 日本臨床化学会年次学術集会
• [Presentation] イノツズマブ オゾガマイシンによる再寛解導入療法後に同種移植を行ったB細胞性急性リンパ性白血病 (2019)
  • Author(s): 松隈雅史, 田中芳紀, 山下浩司, 梶邑泰子, 徳永良洋, 山本薫, 田中真由美, 中邑幸伸, 湯尻俊昭, 谷澤幸生
  • Organizer: 第41回 日本造血細胞移植学会
• [Presentation] JAK2エキソン12変異を含むMPN疾患関連遺伝子変異スクリーニングキットの開発 (2019)
  • Author(s): 高光 恵美, 吉村 翠, 大場 光芳, 山野 博文, 松隈 雅史, 湯尻 俊昭
  • Organizer: 第81回 日本血液学会学術集会
• [Presentation] MPL遺伝子変異陽性ET患者における変異量と臨床経過の検討 (2019)
  • Author(s): 松隈 雅史, 湯尻 俊昭, 梶邑 泰子, 徳永 良洋, 山本 薫, 杉山 暁子, 田中 真由美, 田中 芳紀, 中邑 幸伸, 谷澤 幸生
  • Organizer: 第81回 日本血液学会学術集会