Bone marrow microenvironment and drug resistance in myelodysplastic syndromes

• Project/Area Number: 15K09489
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kitasato University (2016-2018); Jichi Medical University (2015)
• Principal Investigator: SUZUKI TAKAHIRO 北里大学, 医学部, 教授 (40345210)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨髄異形成症候群 / 骨髄微小環境 / 薬剤耐性 / 造血器腫瘍 / 骨髄間葉系細胞

Outline of Final Research Achievements

Myelodysplastic syndrome (MDS) is a hematological malignant disease that is characterized by refractory cytopenias. Malignant cells frequently show resistance to conventional chemotherapeutic drugs, and it is an important issue to overcome the resistance. This research aimed for revealing mechanisms how bone marrow microenvironment affects the resistance of tumor cells in MDS. We found that co-culturing MDS cells with stromal cells gives MDS cells resistance to lenalidomide, but expression of surface adhesion molecules on these cells showed no significant change in the co-culture condition. Our results show that stromal cells do not give drug resistance via expression of adhesion molecules.

Academic Significance and Societal Importance of the Research Achievements

本研究では骨髄異形成症候群（MDS）の腫瘍細胞が骨髄微小環境から薬剤耐性を付与されることについて検討を行った。その結果、del(5q) MDS細胞は骨髄ストローマ細胞によってレナリドミドに対する耐性を付与されることを確認した。表面の接着分子の発現量には変化が認められず、薬剤耐性機序は明確になっていないが、本領域において一つの知見を提供できたものと考えられる。また、本研究では臨床検体からのストローマ細胞の分離の試みも準備を進め、実際の患者における腫瘍と骨髄微小環境の関連を検討する足がかりを形成できたと考えられる。

Research Products

• [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] Dasatinib-associated reversible demyelinating peripheral polyneuropathy in a case of chronic myeloid leukemia. (2018)
  • Author(s): Ishida T, Akagawa N, Miyata T, Tominaga N, Iizuka T, Higashihara M, Suzuki T, Miyazaki K
  • Journal Title: Int J Hematol. Volume: 107 Issue: 3 Pages: 373-377
  • DOI: 10.1007/s12185-017-2339-5
  • Peer Reviewed
• [Journal Article] Reference guide for adult chronic neutropenia (2018)
  • Author(s): 横山 泰久、千葉 滋、日本医療研究開発機構・難治性疾患実用化研究事業「成人慢性好中球減少症の診療ガイドライン作成に向けた予後追跡調査」研究班、高見 昭良、森 康雄、佐藤 信也、鈴木 隆浩、五所 正彦、小原 直、宮﨑 泰司、赤司 浩一
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 7 Pages: 845-857
  • DOI: 10.11406/rinketsu.59.845
  • NAID: 130007430620
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis (2017)
  • Author(s): Kamata H, Tsukasaki Y, Sakai T, Ikebe R, Wang J, Jeffers A, Boren J, Owens S, Suzuki T, Higashihara M, Idell S, Tucker TA, Ikebe M.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 4556-4556
  • DOI: 10.1038/s41598-017-04437-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with myelodysplastic syndrome (2017)
  • Author(s): Ueda Yasunori、Ogura Michinori、Miyakoshi Shigesaburo、Suzuki Takahiro、Heike Yuji、Tagashira Shuzo、Tsuchiya Satoru、Ohyashiki Kazuma、Miyazaki Yasushi
  • Journal Title: Cancer Science Volume: 108 Issue: 12 Pages: 2445-2453
  • DOI: 10.1111/cas.13409
  • 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] Iron overload patients with unknown etiology from national survey in Japan. (2017)
  • Author(s): Ikuta K, Hatayama M, Addo L, Toki Y, Sasaki K, Tatsumi Y, Hattori A, Kato A, Kato K, Hayashi H, Suzuki T, Kobune M, Tsutsui M, Gotoh A, Aota Y, Matsuura M, Hamada Y, Tokuda T, Komatsu N, Kohgo Y.
  • Journal Title: International Journal of Hematology Volume: 105 Issue: 3 Pages: 353-360
  • DOI: 10.1007/s12185-016-2141-9
  • NAID: 120006425801
  • Peer Reviewed
• [Journal Article] The prognostic significance of rapid peripheral blood blast clearance during the initial course of induction chemotherapy in young patients with de novo acute myeloid leukemia. (2016)
  • Author(s): Nakano H, Fujiwara SI, Ito S, Mashima K, Umino K, Minakata D, Yamasaki R, Kawasaki Y, Sugimoto M, Ashizawa M, Yamamoto C, Hatano K, Okazuka K, Sato K, Oh I, Ohmine K, Suzuki T, Muroi K, Kanda Y
  • Journal Title: Hematol Oncol. Volume: in press Issue: 3 Pages: 1-1
  • DOI: 10.1002/hon.2277
  • Peer Reviewed
• [Journal Article] Efficacy of combination therapy with anti-thymocyte globulin and cyclosporine A as a first-line treatment in adult patients with aplastic anemia: a comparison of rabbit and horse formulations. (2016)
  • Author(s): Suzuki T, Kobayashi H, Kawasaki Y, Okazuka K, Hatano K, Fujiwara S, Oh I, Ohmine K, Kanda Y.
  • Journal Title: Int J Hematol Volume: 104 Issue: 4 Pages: 446-53
  • DOI: 10.1007/s12185-016-2046-7
  • Peer Reviewed
• [Journal Article] Retrospective evaluation of the MEAM regimen as a conditioning regimen before autologous peripheral blood stem cell transplantation for lymphoma in two centers with different dosing schedules of melphalan. (2016)
  • Author(s): Sugimoto M, Ito S, Mashima K, Umino K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Ashizawa M, Yamamoto C, Fujiwara SI, Okazuka K, Hatano K, Sato K, Oh I, Ohmine K, Suzuki T, Muroi K, Kako S, Kanda Y.
  • Journal Title: Ann Hematol. Volume: 95 Issue: 9 Pages: 1513-9
  • DOI: 10.1007/s00277-016-2740-9
  • Peer Reviewed
• [Journal Article] Prognostic significance of Wilms tumor 1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. (2016)
  • Author(s): Kobayashi S, Ueda Y, Nannya Y, Shibayama H, Tamura H, Ogata K, Akatsuka Y, Usuki K, Ito Y, Okada M, Suzuki T, Hata T, Matsuda A, Tohyama K, et al.
  • Journal Title: Cancer Biomarkers Volume: in press Issue: 1 Pages: 1-12
  • DOI: 10.3233/cbm-160612
  • Peer Reviewed / Open Access
• [Journal Article] 鉄剤不応の鉄欠乏性貧血 (2016)
  • Author(s): 鈴木隆浩
  • Journal Title: 臨床血液 Volume: 57 Pages: 1881-1889
  • NAID: 130005420649
• [Journal Article] A low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor priming regimen versus a daunorubicin plus cytarabine regimen as induction therapy for older patients with acute myeloid leukemia: A propensity score analysis. (2016)
  • Author(s): Minakata D, Fujiwara SI, Ito S, Mashima K, Umino K, Nakano H, Kawasaki Y, Sugimoto M, Yamasaki R, Yamamoto C, Ashizawa M, Hatano K, Okazuka K, Sato K, Oh I, Ohmine K, Suzuki T, Muroi K, Kanda Y
  • Journal Title: Leuk Res. Volume: 42 Pages: 82-87
  • DOI: 10.1016/j.leukres.2015.12.013
  • Peer Reviewed
• [Journal Article] Dose-reduced combination of mitoxantrone, etoposide, and cytarabine (miniMEC) for relapsed and refractory acute leukemia. (2016)
  • Author(s): Yamamoto C, Ito S, Mashima K, Umino K, Minakata D, Yamasaki R, Kawasaki Y, Sugimoto M, Nakano H, Ashizawa M, Okazuka K, Hatano K, Sato K, Oh I, Fujiwara S, Ohmine K, Suzuki T, Muroi K, Kanda Y
  • Journal Title: Leuk Lymphoma Volume: in press
  • Peer Reviewed
• [Journal Article] Distribution of serum erythropoietin levels in Japanese patients with myelodysplastic syndromes. (2015)
  • Author(s): Suzuki T, Oh I, Ohmine K, Meguro A, Mori M, Fujiwara S, Yamamoto C, Nagai T, Ozawa K.
  • Journal Title: Int J Hematol. Volume: 101 Issue: 1 Pages: 32-36
  • DOI: 10.1007/s12185-014-1699-3
  • Peer Reviewed / Open Access
• [Journal Article] MDSの治療－薬物療法・移植・支持療法－ (2015)
  • Author(s): 鈴木隆浩
  • Journal Title: 臨床血液 Volume: 56 Pages: 1985-1995
  • NAID: 130005103292
• [Presentation] 骨髄異形成症候群 ―診断のポイント― (2018)
  • Author(s): 鈴木隆浩
  • Organizer: 第19回 日本検査血液学会学術集会
  • Invited
• [Presentation] A nation-wide study of adult chronic neutropenia in Japan: 2nd report (2018)
  • Author(s): 横山泰久、小原直、五所正彦、鈴木隆浩、高見昭良、宮崎泰司、赤司浩一、千葉滋
  • Organizer: 第80回 日本血液学会学術集会
• [Presentation] MDSの病態と診療－最近の話題－ (2018)
  • Author(s): 鈴木隆浩
  • Organizer: 第125回 日本血液学会東北地方会
  • Invited
• [Presentation] Characteristics of palliative home care for hematological tumors in comparison with solid tumors (2018)
  • Author(s): 大橋晃太、石田隆、翁千香子、大橋志保、翁祖誠、宮崎浩二、鈴木隆浩
  • Organizer: 第80回 日本血液学会学術集会
• [Presentation] Expression of adhesion molecules in intravascular lymphoma: histopathological review of our cases (2018)
  • Author(s): 小倉慎司、秋谷昌史、堀米祐一、吉田功、翁祖誠、田寺範行、石田隆、道下雄介、横山真喜、鎌田浩稔、宮崎浩二、村雲芳樹、鈴木隆浩
  • Organizer: 第80回 日本血液学会学術集会
• [Presentation] 鉄と造血 ～鉄欠乏と鉄過剰～ (2017)
  • Author(s): 鈴木隆浩
  • Organizer: 第62回日本透析医学会学術集会
  • Invited
• [Presentation] 貧血症例の診断と骨髄異形成症候群 (2017)
  • Author(s): 鈴木隆浩
  • Organizer: 第18回日本検査血液学会学術集会
  • Invited
• [Presentation] Analysis of the prevalence and risk factors of adult neutropenia in a large cohort in Japan. (2017)
  • Author(s): 横山泰久，五所正彦，佐藤信也，森康雄，鈴木隆浩,高見昭良，宮崎康司，赤司浩一，千葉滋
  • Organizer: 第79回 日本血液学会学術集会
• [Presentation] Successful management of CML-AP with thrombocytopenia harboring T315I mutation by ponatinib. (2017)
  • Author(s): 岩瀬諒子，石田隆，羽山慧以，川田孝平，道下雄介，小倉慎司，堀米祐一，田寺範行，翁祖誠，東原正明，宮﨑浩二，鈴木隆浩
  • Organizer: 第79回 日本血液学会学術集会
• [Presentation] Ibrutinib ameliorated refractory immune-mediated thrombocytopenia associated with CD8+CD19+ B cell CLL. (2017)
  • Author(s): 塩野祐，石田隆，横山真喜，翁祖誠，道下雄介，小倉慎司，堀米祐一，田寺範行，宮﨑浩二，鈴木隆浩
  • Organizer: 第79回 日本血液学会学術集会
• [Presentation] MDS分類と治療の進化. (2016)
  • Author(s): 鈴木隆浩
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] 鉄剤不応の鉄欠乏性貧血 (2016)
  • Author(s): 鈴木隆浩
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] MDSの病態と治療－最近の話題－. (2016)
  • Author(s): 鈴木隆浩
  • Organizer: 日本輸血・細胞治療学会 東北支部例会
  • Place of Presentation: 山形テルサ（山形市)
  • Invited
• [Presentation] 骨髄異形成症候群（MDS）－診療の基礎と最近の進歩 (2016)
  • Author(s): 鈴木隆浩
  • Organizer: 第54回 日本内科学会関東支部主催 生涯教育講演会
  • Place of Presentation: 日本都市センター（東京）
  • Invited
• [Presentation] A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS) (2015)
  • Author(s): Suzuki T, Ueda Y, Ogura M, Uchida T, Ozawa K, Miyakoshi S, Naoe T, Murata M, Kizaki M, Uike N, Abe Y, Hidaka M, Tagashira S, Tsuchiya S, Ohyashiki K, Miyazaki Y.
  • Organizer: The American Society of Hematology 57th Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] MDSの治療－薬物療法・移植・支持療法－ (2015)
  • Author(s): 鈴木隆浩
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂他（金沢）
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] High-dose methotrexate-based multi-agent chemotherapy for systemic lymphoma with CNS involvement. (2015)
  • Author(s): Umino K, Fujiwara S, Sato K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Yamamoto C, Takizawa H, Hatano K, Okazuka K, Oh I, Ohmine K, Suzuki T, Nagai T, Muroi K, Kanda Y
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 石川県立音楽堂他（金沢）
  • Year and Date: 2015-10-16
• [Presentation] Dose-reduced combination of MIT, ETP, and AraC(miniMEC) for relapsed and refractory acute leukemia (2015)
  • Author(s): Yamamoto C, Umino K, Minakata D, Yamasaki R, Kawasaki Y, Sugimoto M, Takizawa H, Hatano K, Okazuka K, Sato K, Oh I, Fujiwara S, Ohmine K, Suzuki T, Nagai T, Muroi K, Kanda Y
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 石川県立音楽堂他（金沢）
  • Year and Date: 2015-10-16
• [Presentation] Rapid decline in peripheral blood blast ratio predicts complete remission in patients with AML. (2015)
  • Author(s): Nakano H, Umino K, Minakata D, Yamasaki R, Kawasaki Y, Sugimoto M, Yamamoto C, Takizawa H, Hatano K, Okazuka H, Sato K, Oh I, Fujiwara S, Ohmine K, Suzuki T, Nagai T, Muroi K, Kanda Y
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 石川県立音楽堂他（金沢）
  • Year and Date: 2015-10-16