Molecular mechanisms of leukemic transformation of myelodysplastic syndromes.

• Project/Area Number: 17K09026
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: TOHYAMA Kaoru 川崎医科大学, 医学部, 教授 (80227561)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 骨髄異形成症候群 / 白血病化 / 遺伝子変異 / 網羅的ゲノム解析 / 網羅的遺伝子解析 / ゲノム / 造血障害 / 白血病移行 / 遺伝子 / 内科

Outline of Final Research Achievements

We established MDS92 cell line from a patient with myelodysplastic syndromes (MDS), and 5 sublines including MDS-L were isolated from MDS92. Further, MDS-L-2007 and MDS-LGF were obtained from MDS-L in the presence and absence of IL-3, respectively. Whole exome analyses demonstrated:TP53 mutation was found in the patient sample and was inherited by subsequent cell lines; CEBPA mutation was present in a part of the sample fraction; NRAS mutation emerged during culture. Such accumulated mutations could cause establishment of MDS92 cell line. Histone-H3(K27M) mutation (H3-K27M) was newly detected in MDS-L. MDS-L cells were a mixture of H3-K27M-mutant and wild-type clones, and this mutation was inherited by MDS-L-2007 but not MDS-LGF. H3-K27M-mutant clones exerted growth advantage in the presence of IL-3 but did not without IL-3 probably because of strict IL-3 dependency of the mutant clones. We propose this series of cell lines as an in vitro model for leukemic evolution of MDS.

Academic Significance and Societal Importance of the Research Achievements

中高齢者に好発する血液難病であるMDSは急性白血病に移行すると著しく予後不良であり、この疾患の克服は社会的にも重要課題である。本研究は世界的にユニークなMDS細胞株およびそこから派生した急性白血病細胞株を用いて、MDSから急性白血病へ移行する分子機構の一端を解明したという学術的価値の高い内容である。また細胞株研究では新規薬剤の基礎的検討が繰り返し可能なことから、今後新たな治療法の開拓によってこの疾患の克服に繋げるという社会的にも期待できる成果といえる。

Research Products

• [Int'l Joint Research] City of Hope Medical Center(米国)
• [Journal Article] The augmented expression of the cytidine deaminase gene by 5-azacytidine predicts therapeutic efficacy in myelodysplastic syndromes (2019)
  • Author(s): Murakami Yuichi、Kimura Yoshizo、Kawahara Akihiko、Mitsuyasu Shohei、Miyake Hidetoshi、Tohyama Kaoru、Endo Yoshio、Yoshida Nao、Imamura Yutaka、Watari Kosuke、Ono Mayumi、Okamura Takashi、Kuwano Michihiko
  • Journal Title: Oncotarget Volume: 10 Issue: 23 Pages: 2270-2281
  • DOI: 10.18632/oncotarget.26784
  • Peer Reviewed
• [Journal Article] Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway. (2019)
  • Author(s): Sakakibara Kanae, Tsujioka Takayuki, Kida Jun-ichiro, Kurozumi Nami, Nakahara Takako, Suemori Shin-ichiro, Kitanaka Akira, Arao Yujiro, Tohyama Kaoru
  • Journal Title: Int J Hematol Volume: 110 Pages: 213-227
  • Peer Reviewed
• [Journal Article] MDS細胞株とその亜株による研究応用 (2019)
  • Author(s): 通山 薫
  • Journal Title: 血液内科 Volume: 78 Pages: 731-736
  • NAID: 40021930439
• [Journal Article] Present status and perspective of laboratory hematology in Japan: On the standardization of blood cell morphology including myelodysplasia: On behalf of the Japanese Society for Laboratory Hematology (2018)
  • Author(s): Tohyama K.
  • Journal Title: International Journal of Laboratory Hematology Volume: 40 Issue: S1 Pages: 120-125
  • DOI: 10.1111/ijlh.12819
  • Peer Reviewed
• [Journal Article] Interobserver concordance of assessments of dysplasia and blast counts for the diagnosis of patients with cytopenia: From the Japanese central review study (2018)
  • Author(s): Matsuda A, Kawabata H, Tohyama K, Maeda T, Araseki K, Hata T, Suzuki T, Kayano H, Shimbo K, Usuki K, Chiba S, Ishikawa T, Arima N, Nohgawa M, Ohta A, Miyazaki Y, Nakao S, Ozawa K, Arai S, Kurokawa M, Mitani K, Takaori-Kondo A
  • Journal Title: Leukemia Research Volume: 74 Pages: 137-143
  • DOI: 10.1016/j.leukres.2018.06.003
  • Peer Reviewed
• [Journal Article] An MDS-derived cell line and a series of its sublines serve as an in vitro model for the leukemic evolution of MDS (2018)
  • Author(s): Kida Jun-ichiro、Tsujioka Takayuki、Suemori Shin-ichiro、Okamoto Shuichiro、Sakakibara Kanae、Takahata Takayuki、Yamauchi Takahiro、Kitanaka Akira、Tohyama Yumi、Tohyama Kaoru
  • Journal Title: Leukemia Volume: 32 Issue: 8 Pages: 1846-1850
  • DOI: 10.1038/s41375-018-0189-7
  • Peer Reviewed
• [Journal Article] SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function (2018)
  • Author(s): Sun J, He X, Zhu Y, Ding Z, Dong H, Feng Y, Du J, Wang H, Wu X, Zhang L, Yu X, Lin A, McDonald T, Zhao D, Wu H, Hua WK, Zhang B, Feng L, Tohyama K, Bhatia R, Oberdoerffer P, Chung YJ, Aplan PD, Boultwood J, Pellagatti A, Khaled S, Kortylewski M, Pichiorri F, Kuo YH, Carlesso N, Marcucci G, Jin H, Li L
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 3 Pages: 355-369.e9
  • DOI: 10.1016/j.stem.2018.07.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] KIF20A, highly expressed in immature hematopoietic cells, supports the growth of HL60 cell line (2018)
  • Author(s): Morita Hiroyuki、Matsuoka Akihito、Kida Jun-ichiro、Tabata Hiroyuki、Tohyama Kaoru、Tohyama Yumi
  • Journal Title: International Journal of Hematology Volume: 108 Issue: 6 Pages: 607-614
  • DOI: 10.1007/s12185-018-2527-y
  • Peer Reviewed
• [Journal Article] Validation of the revised International Prognostic Scoring System in patients with myelodysplastic syndrome in Japan: results from a prospective multicenter registry (2017)
  • Author(s): Kawabata H, Tohyama K, Matsuda A, Araseki K, Hata T, Suzuki T, Kayano H, Shimbo K, Zaike Y, Usuki K, Chiba S, Ishikawa T, Arima N, Nogawa M, Ohta A, Miyazaki Y, Mitani K, Ozawa K, Arai S, Kurokawa M, Takaori-Kondo A
  • Journal Title: International Journal of Hematology Volume: 106 Issue: 3 Pages: 375-384
  • DOI: 10.1007/s12185-017-2250-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q). (2017)
  • Author(s): Li L, Sheng Y, Li W, Hu C, Mittal N, Tohyama K, Seba A, Zhao YY, Ozer H, Zhu T, Qian Z
  • Journal Title: Cancer Research Volume: 77 Issue: 15 Pages: 4116-4126
  • DOI: 10.1158/0008-5472.can-17-0202
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study) (2017)
  • Author(s): Kobayashi T, Nannya Y, Ichikawa M, Oritani K, Kanakura Y, Tomita A, Kiyoi H, Kobune M, Kato J, Kawabata H, Shindo M, Torimoto Y, Yonemura Y, Tohyama K, et al
  • Journal Title: American Journal of Hematology Volume: 92 Issue: 12 Pages: 1324-1332
  • DOI: 10.1002/ajh.24905
  • Peer Reviewed / Open Access
• [Journal Article] Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A (2017)
  • Author(s): Oben KZ, Alhakeem SS, McKenna MK, Brandon JA, Mani R, Noothi SK, Jinpeng L, Akunuru S, Dhar SK, Singh IP, Liang Y, Wang C, Abdel-Latif A, Stills HF Jr, St Clair DK, Geiger H, Muthusamy N, Tohyama K, Gupta RC, Bondada S.
  • Journal Title: Oncotarget Volume: 8 Issue: 44 Pages: 77436-77452
  • DOI: 10.18632/oncotarget.20497
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 骨髄異形成症候群（MDS）の形態診断---WHO分類2017年版を踏まえて (2019)
  • Author(s): 通山 薫
  • Organizer: 第58回日本血液学会中国四国地方会
  • Invited
• [Presentation] MDSの形態診断～～異形成との遭遇 (2019)
  • Author(s): 通山 薫
  • Organizer: 第10回日本血液学会関東甲信越地方会
  • Invited
• [Presentation] 臨床検査からのメッセージ ～～ さまざまなご縁とともに (2019)
  • Author(s): 通山 薫
  • Organizer: 第66回日本臨床検査医学会学術集会
  • Invited
• [Presentation] Challenges in laboratory hematology in different regions of the world: Perspectives from Japan. (2018)
  • Author(s): Kaoru Tohyama
  • Organizer: ISLH 2018 in Brussels
  • Int'l Joint Research / Invited
• [Presentation] 骨髄異形成症候群（MDS）の形態診断---WHO分類2017年版をふまえて (2018)
  • Author(s): 通山 薫
  • Organizer: 第9回日本血液学会関東甲信越地方会
  • Invited
• [Presentation] 骨髄異形成症候群（MDS）の形態診断---WHO分類2017年版を踏まえて (2018)
  • Author(s): 通山 薫
  • Organizer: 第58回日本血液学会中国四国地方会
  • Invited
• [Book] 血液細胞アトラス 第6版 (2018)
  • Author(s): 通山 薫、張替秀郎
  • Total Pages: 418
  • Publisher: 文光堂
  • ISBN: 9784830614262
• [Remarks] 川崎医科大学 検査診断学教室
  • URL: http://www.kawasaki-m.ac.jp/lh/
• [Remarks] 川崎医科大學検査診断学教室ホームペ－ジ
  • URL: http://www.kawasaki-m.ac.jp/lh/
• [Remarks] 川崎医科大学 検査診断学教室ホームページ
  • URL: http://www.kawasaki-m.ac.jp/lh/