Analysis of the resistant mechanism of AML stem cells for tyrosine kinase inhibitor in bone marrow microenvironment

• Project/Area Number: 23591537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Okayama University (2012-2013); Nagoya University (2011)
• Principal Investigator: SHIMADA AKIRA 岡山大学, 大学病院, 講師 (70391836)
• Co-Investigator(Kenkyū-buntansha): HAYASHI Yasuhide 群馬県衛生環境研究所, 研究企画係, 研究員 (30238133)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: AML / TKI / MSC / drug resistance / 抗メチル化薬 / HDAC阻害剤 / チロシンキナーゼ / 薬剤耐性 / FLT3 / 骨髄微小環境 / JAK阻害剤

Research Abstract

The mechanism of drug resistance for Tyrosine kinase inhibitor (TKI) in AML cells remains unkown. AML cells showed the drug resistance in coculture model with mesenchimal stroma cells(MSCs). AML cells became more resistant for TKI in direct contact with MSC than in floating condition. For this reason, adhesion molecule such as integrin, or several cytokines and chemokines affected the up-regulation of AKT, MAPK and JAK/STAT signaling pathway. When AML cells were cocultured with MSC for more than 4 weeks, the fraction of side population increased and showed TKI resistance. To overcome this drug resistance, we found the synergistic effect in TKI with PI3K/mROR/AKT inhibitor or in TKI with JAK/STAT inhibitor.

Research Products

• [Journal Article] ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases (2014)
  • Author(s): Aoe M, Shimada A, Muraoka M, Washio K, Nakamura Y, Takahashi T, Imada M, Watanabe T, Okada K, Nishiuchi R, Ishida T, Miyamura T, Chayama K, Shibakura M, Oda M, Morishima T.
  • Journal Title: Int J Hematol Volume: 99 Issue: 5 Pages: 609-15
  • DOI: 10.1007/s12185-014-1565-3
  • Peer Reviewed / Open Access
• [Journal Article] RUNX1 mutation associated with clonal evolution in relapsed pediatric acute myeloid leukemia with t(16;21)(p11;q22). (2014)
  • Author(s): Ismael O, Shimada A, Elmahdi S, Elshazley M, Muramatsu H, Hama A, Takahashi Y, Yamada M, Yamashita Y, Horibe K, Kojima S.
  • Journal Title: Int J Hematol Volume: 99 Issue: 2 Pages: 169-174
  • DOI: 10.1007/s12185-013-1495-5
  • Peer Reviewed
• [Journal Article] Detection of RBM15-MKL1 fusion was useful for diagnosis and monitoring of minimal residual disease in infant acute megakaryobastic leukemia. (2014)
  • Author(s): Takeda A, Shimada A, et al. Hamamoto K, Yoshino S, Nagai T, Fujii Y, Yamada M, Nakamura Y, Watanabe T, Watanabe Y, Yamamoto Y, Sakakibara K, Oda M, Morishima T.
  • Journal Title: Acta Med. Okayama Volume: 68 Pages: 119-123
  • Peer Reviewed
• [Journal Article] ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases. (2014)
  • Author(s): Aoe M, Shimada A, Muraoka M, Washio K, Nakamura Y, Takahashi T, Imada M, Watanabe T, Okada K, Nishiuchi R, Ishida T, Miyamura T, Chayama K, Shibakura M, Oda M, Morishima T.
  • Journal Title: Int J Hematol Volume: in press
  • Peer Reviewed
• [Journal Article] Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Saito AM, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Kiyokawa N, Isoyama, K, Mizutani S, Hara J, Horibe K, Nakahata T, Adachi S.
  • Journal Title: Int J Hematol Volume: 98 Issue: 5 Pages: 578-588
  • DOI: 10.1007/s12185-013-1429-2
  • Peer Reviewed
• [Journal Article] WT1 mutation in pediatric patients with acute myeloid leukemia: A study of the Japanese Childhood AML Cooperative Study Group (2013)
  • Author(s): Sano H, Shimada A, Tabuchi K, Taki T, Murata C, Park M, Sotomatsu Tawa A, Kobayashi R, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y
  • Journal Title: Int J Hematol Volume: 98 Issue: 4 Pages: 437-445
  • DOI: 10.1007/s12185-013-1409-6
  • Peer Reviewed
• [Journal Article] Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children. (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Moriya-Saito A, Kudo K, Taga T, Iwamoto S, Shimada A, , Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Kigasawa H, Kosaka Y, Miyachi H, Horibe K, Nakahata T, and Adachi S.
  • Journal Title: Leukemia Volume: 27 Issue: 12 Pages: 2413-2416
  • DOI: 10.1038/leu.2013.153
  • Peer Reviewed
• [Journal Article] NUP98-NSD1 related gene expression signature is strongly associated with a poor prognosis in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group Cooperative Study Group (2013)
  • Author(s): Shiba N, Ichikawa H, Taki T, Park M, Jo A, Mitani S, Shimada A, Sotomatsu M, Arakawa H, Tabuchi K, Adachi S, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y
  • Journal Title: Genes Chromosomes Cancer Volume: 52 Issue: 7 Pages: 683-693
  • DOI: 10.1002/gcc.22064
  • Peer Reviewed
• [Journal Article] High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group (2012)
  • Author(s): Shimada A, Taki T, Koga D, Tabuchi K, Tawa A, Hanada R, Tsuchida M, Horibe K, Tsukimoto I, Adachi S, Kojima S, Hayashi Y
  • Journal Title: Int J Hematol Volume: 96 Issue: 4 Pages: 469-476
  • DOI: 10.1007/s12185-012-1163-1
  • NAID: 10031126738
  • Peer Reviewed
• [Journal Article] Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003–06 from the Japan Association of Childhood Leukaemia Study. (2012)
  • Author(s): Imamura T, Adachi S, et al.
  • Journal Title: British Journal of Haematology Volume: 159 Issue: 2 Pages: 204-210
  • DOI: 10.1111/bjh.12030
  • Peer Reviewed
• [Journal Article] Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. (2012)
  • Author(s): Taga T, Adachi S, et al.
  • Journal Title: Blood Volume: 120 Issue: 9 Pages: 1810-1815
  • DOI: 10.1182/blood-2012-03-414755
  • Peer Reviewed
• [Journal Article] Childhood acute myeloid leukemia with bone marrow eosinophilia caused by t(16;21)(q24;q22) (2012)
  • Author(s): Kawashima N, Shimada A, Taketani T, Hayashi Y, Yoshida N, Matsumoto K, Takahashi Y, Kojima S, Kato K
  • Journal Title: Int J Hematol Volume: 95 Issue: 5 Pages: 577-580
  • DOI: 10.1007/s12185-012-1044-7
  • NAID: 10030633418
  • Peer Reviewed
• [Journal Article] RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse : a study of the Japanese Childhood AML Cooperative Study Group (2012)
  • Author(s): Sano H, Shimada A, Taki T, Murata C, Park MJ, Sotomatsu M, Tabuchi K, Tawa A, Kobayashi R, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y.
  • Journal Title: Int J Hematol Volume: 95 Issue: 5 Pages: 509-515
  • DOI: 10.1007/s12185-012-1033-x
  • NAID: 10030633077
  • Peer Reviewed
• [Journal Article] Molecular lesions in childhood and adult acute megakaryoblastic leukemia (2012)
  • Author(s): Hama A, Muramatsu H, Makishima H, Sugimoto Y, Szpurka H, Jasek M, O'Keefe C, Takahashi Y, Sakaguchi H, Doisaki S, Shimada A, Watanabe N, Kato K, Kojima S, Maciejewski JP.
  • Journal Title: Br J. Haematol Volume: 156 Issue: 3 Pages: 316-25
  • DOI: 10.1111/j.1365-2141.2011.08948.x
  • Peer Reviewed
• [Journal Article] Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia (2012)
  • Author(s): Doisaki S, Muramatsu H, Shimada A, Takahashi Y, Mori-Ezaki M, Sato M, Kawaguchi H, Kinoshita A, Sotomatsu M, Hayashi Y, Furukawa-Hibi Y, Yamada K, Hoshino H, Kiyoi H, Yoshida N, Sakaguchi H, Narita A, Wang X, Ismael O, Xu Y, Nishio N, Tanaka M, Hama A, Koike K, Kojima S
  • Journal Title: Blood Volume: 120 Issue: 7 Pages: 1485-1488
  • DOI: 10.1182/blood-2012-02-406090
  • Peer Reviewed
• [Presentation] Poor prognosis with different induction rate was observed in children with acute myeloid leukemia and FLT3-ITD according to the ITD/WT allelic ratio: a result from the Japanese Pediatric Leukemia/Lymphoma Study Group (2014)
  • Author(s): Shimada A, Yamashita Y, Tomizawa D, et al
  • Organizer: ASH Annual Meeting
  • Place of Presentation: NewOrleans, USA
• [Presentation] Analysis of ABL kinase mutation in 4 pediatric philadelphia chromosome-positive acute lymphoblastic leukemia (2014)
  • Author(s): Aoe M, Shimada A, Muraoka M, et al
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Chemotherapy prior to HSCT is effective for pediatric RAEB/RAEB-T (2014)
  • Author(s): Shimada A, Kinoshita A, Manabe A, et al
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Persistent Chromosomal Abnormalities in Ph-negative cellsduring Imatinib Therapy-aCML case (2014)
  • Author(s): Muraoka M, Shimada A, Watanabe T, et al
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Poor prognosis with different induction rate was observed in children with acute myeloid leukemia and FLT3-ITD according to the ITD/WT allelic ratio: a result from the Japanese Pediatric Leukemia/Lymphoma Study Group (2013)
  • Author(s): Akira Shimada, Yuka Yamashita, Daisuke Tomizawa, et al.
  • Organizer: 米国血液学会
  • Place of Presentation: NewOrleans, USA
• [Presentation] 小児Ph陽性急性リンパ性白血病４例のABLキナーゼ変異解析 (2013)
  • Author(s): 青江伯規、嶋田 明、村岡倫子、鷲尾佳奈、中村佳弥、高橋孝英、今田昌秀、渡部俊幸、岡田 健、西内律雄、宮村能子、茶山公祐、小田 慈、森島恒雄
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Chemotherapy prior to Hematopoietic stem cell transplantation (2013)
  • Author(s): Akira Shimada, Akitoshi Kinoshita, Atsushi Manabe, Miharu Yabe, Hayato Miyachi, Hiromichi Matsushita, Tomohiko Taki, Masami Inoue, Daisuke Hasegawa, Asahito Hama, Masafumi Ito, Akio Tawa , Seiji Kojima, Souich Adachi
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Persistent Chromosomal Abnormalities in Ph-negative cells during Imatinib Therapy - a CML case (2013)
  • Author(s): Michiko Muraoka, Akira Shimada, Toshio Watanabe, Sato Imajo, Yui Kanazawa, Kana Washio, Ritsuo Nishiuchi, Takako Miyamura, Kosuke Chayama， Megumu Oda， Tsuneo Morishima
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌
• [Presentation] 小児の骨髄増殖性疾患(MPN)PV/ET/CMML/HES/CELについて (2012)
  • Author(s): 嶋田 明、小島勢二
  • Organizer: 日本小児科学会
  • Place of Presentation: 福岡
• [Presentation] Pediatric Myeloid Malignancy and Related Diseases-AML/MDS/MPD. Pediatric AML Symposium (2012)
  • Author(s): Shimada A.
  • Organizer: Samusung Medical Center
  • Place of Presentation: Seoul, Korea
• [Presentation] High FLT3 mRNA expression without FLT3-ITD in infants with acute myeloid leukemia (2012)
  • Author(s): Shimada A, Yamada M, Yamashita Y, et al
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Chicago, USA
• [Presentation] Pediatric Myeloid Malignancy and Related Diseases-AML/MDS/MPD (2012)
  • Author(s): Akira SHIMADA
  • Organizer: Samuung Medical Center, Pediatric cancer Conference
  • Place of Presentation: Seoul/韓国
  • Invited
• [Presentation] High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: A study of the Japanese Childhood AML Cooperative Study Group (2012)
  • Author(s): Akira Shimada, Tomohiko Taki, Daisuke Koga, Ken Tabuchi, Akio Tawa, Ryoji Hanada, Masahiro Tsuchida, Keizo Horibe, Ichiro Tsukimoto, Souichi Adachi, Seiji Kojima, Yasuhide Hayashi
  • Organizer: WT1 International Symposium
  • Place of Presentation: Kyoto
• [Presentation] De novo childhood Myelodysplastic/myeloproliferative unclassifiable disease with unique molecular characteristics (2012)
  • Author(s): Shimada A, Ismael O, Hama A, Muramatsu H, Sakaguchi H, Tanaka M, Takahashi Y, Yinyan X, Fukuda M, Miyajima Y, Yamashita Y, Horibe K, Hanada R, Ito M, Kojima S
  • Organizer: EWOG-MDS 2012
  • Place of Presentation: Pratz/チェコ共和国
• [Presentation] JAK2 V617F mutation in Pediatric Myeloproliferative Neoplasm (2012)
  • Author(s): Akira Shimada, Olfat Ismael, Yinyan Xu, et al.
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Presentation] 小児造血器疾患の分子病態解明と今後の分子標的療法の展望 (2012)
  • Author(s): 嶋田 明
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 横浜
  • Invited
• [Book] 理解して出そう 小児の検査-オーダー・手技・解釈(小児科診療76巻増刊)(血液 骨髄検査) (2013)
  • Author(s): 渡部俊幸,嶋田明
• [Book] 【理解して出そう 小児の検査-オーダー・手技・解釈】 血液 骨髄検査 (2013)
  • Author(s): 渡部 俊幸, 嶋田 明
  • Total Pages: 5
  • Publisher: 小児科診療
• [Book] 白血病・固形腫瘍における分子標的療法 小児造血器疾患の分子病態解明と今後の分子標的療法の展望 (2013)
  • Author(s): 嶋田 明
  • Total Pages: 5
  • Publisher: 日本小児血液・がん学会雑誌
• [Book] 小児急性骨髄性白血病における分子異常と予後(Annual Review血液) (2012)
  • Author(s): 嶋田 明
  • Publisher: 中外医学社
• [Book] Annual Review血液 (2012)
  • Author(s): 嶋田 明
  • Publisher: 中外医学社