Prognostic implication of gene mutations in patients with acute myeloid leukemia

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591136
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kumamoto University
• Principal Investigator: ASOU Norio Kumamoto University, 大学院・生命科学研究部, 准教授 (50175171)
• Project Period (FY): 2008 – 2010
• Keywords: 急性骨髄性白血病 / 正常染色体 / FLT3 / NPM1 / CEBPA / IDH1 / IDH2 / TIS11D / 遺伝子変異 / 予後予測因子 / RNA結合蛋白

Research Abstract

Of 190 patients with acute myeloid leukemia (AML), mutations in the FLT3-ITD, NPM1, and CEBPA genes were detected in 18%, 23% and 12%, respectively. AML patients with FLT3-ITD or without any mutation had a poor clinical outcome. In addition, 8% and 10% showed IDH1 and IDH2 mutations. IDH2 mutation was associated with a poor overall survival. Of patients lacking these mutations, we identified deletion mutations in the RNA binding protein TIS11D. Wild-type TIS11D induced growth inhibition and an S phase checkpoint response, while the deletion mutant showed a diminished effect. We establish the prognostic factors in AML according to these results.

Research Products

• [Journal Article] A randomized comparison of four courses of standard-dose multiagent chemotherapy versus three courses of high-dose cytarabine alone in post-remission therapy for acute myeloid leukemia in adults : the JALSG AML201 study. (2011)
  • Author(s): Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Blood 117 Pages: 2366-2372
  • Peer Reviewed
• [Journal Article] Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia : JALSG AML201 Study. (2011)
  • Author(s): Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R
  • Journal Title: Blood 117 Pages: 2358-2365
  • Peer Reviewed
• [Journal Article] Mutation in the RNA binding protein TIS11D/ZFP36L2 is associated with the pathogenesis of acute leukemia. (2011)
  • Author(s): Iwanaga E, Nanri T, Mitsuya H, Asou N.
  • Journal Title: Int J Oncol 38(1) Pages: 25-31
  • Peer Reviewed
• [Journal Article] Impact of additional chromosomal abnormalities in patients with acute promyelocytic leukemia-10 years' (2011)
  • Author(s): Ono T, Takeshita A, Iwanaga M, Asou N, Naoe T, Ohno R.
  • Journal Title: results of the Japan Adult Leukaemia Study Group APL97 study-Haematologica 96 Pages: 174-176
  • Peer Reviewed
• [Journal Article] Extramedullary tumors presenting double vision in patients with t(8;21) (q22;q22) acute myeloid leukemia lacking mutations in the receptor tyrosine kinase genes KIT or FLT3. (2010)
  • Author(s): Tsuji T, Takatsu N, Nosaka K, Kawakita T, Nanri T, Horikawa K, Mitsuya H, Asou N.
  • Journal Title: Leuk Res 34 Pages: e320-e322
  • Peer Reviewed
• [Journal Article] Successful treatment with low-dose imatinib mesylate of therapy-related myeloid neoplasm harboring TEL-PDGFRB in a patient with acute promyelocytic leukemia. (2010)
  • Author(s): Asou N, Iwanaga E, Nanri T, Mitsuya H.
  • Journal Title: Haematologica 95 Pages: e1-e2
  • Peer Reviewed
• [Journal Article] Successful treatment of Aspergillus liver abscesses in a patient with acute monoblastic leukemia using combination antifungal therapy including micafungin as a key drug. (2010)
  • Author(s): Yamada R, Horikawa K, Ishihara S, Hoshino K, Kawaguchi T, Iyama K, Mitsuya H, Asou N.
  • Journal Title: Int J Hematol 91 Pages: 711-715
  • Peer Reviewed
• [Journal Article] Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor for elderly patients with previously untreated acute myeloid leukemia. (2010)
  • Author(s): Suzushima H, Wada N, Yamasaki H, Eto K, Shimomura T, Kugimiya MH, Horikawa K, Nishimura S, Tsuda H, Mitsuya H, Asou N.
  • Journal Title: Leuk Res 34 Pages: 610-614
  • Peer Reviewed
• [Journal Article] Allogeneic stem cell transplantation versus chemotherapy as post-remission therapy for intermediate or poor risk adult acute myeloid leukemia : results of the JALSG AML97 study. (2010)
  • Author(s): Sakamaki H, Miyawaki S, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Takahashi M, Ogawa Y, Honda S, Ohno R.
  • Journal Title: Int J Hematol 91 Pages: 284-292
  • Peer Reviewed
• [Journal Article] Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia : the JALSG AML95 study. (2010)
  • Author(s): Ohtake S, Miyawaki S, Kiyoi H, Miyazaki Y, Okumura H, Matsuda S, Nagai T, Kishimoto Y, Okada M, Takahashi M, Handa H, Takeuchi J, Kageyama S, Asou N, Yagasaki F, Maeda Y, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Int J Hematol 91 Pages: 276-283
  • Peer Reviewed
• [Journal Article] Stem cell exhaustion due to Runxl deficiency is prevented by Evi5 activation in leukemogenesis. (2010)
  • Author(s): Jacob B, Osato M, Yamashita N, Wang CQ, Taniuchi I, Littman DR, Asou N, Ito Y.
  • Journal Title: Blood 115 Pages: 1610-1620
  • Peer Reviewed
• [Journal Article] A family harboring a germ-line N-terminal C/EBPα mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPα mutation. (2010)
  • Author(s): Nanri T, Uike N, Kawakita T, Iwanaga E, Mitsuya H, Asou N.
  • Journal Title: Genes Chromosomes Cancer 49 Pages: 237-241
  • Peer Reviewed
• [Journal Article] Hairy cell leukemia responsive to anti-thymocyte globulin used as immunosuppressive therapy for aplastic anemia. (2009)
  • Author(s): Fujiwara S, Miyake H, Nosaka K, Yoshida M, Ishihara S, Horikawa K, Yonemura Y, Iyama K, Mitsuya H, Asou N.
  • Journal Title: Int J Hematol 90 Pages: 471-475
  • Peer Reviewed
• [Journal Article] Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML. (2009)
  • Author(s): Powell JA, Thomas D, Barry EF, Kok CH, McClure BJ, Tsykin A, To LB, Brown A, Lewis ID, Herbert K, Goodall GJ, Speed TP, Asou N, Jacob B, Osato M, Haylock DN, Nilsson SK, D'Andrea RJ, Lopez AF, Guthridge MA.
  • Journal Title: Blood 114 Pages: 4859-4870
  • Peer Reviewed
• [Journal Article] Acute promyelocytic leukemia harboring a STAT5B-RARA fusion gene and a G596V missense mutation in the STAT5B SH2 domain of the STAT5B-RARA. (2009)
  • Author(s): Iwanaga E, Nakamura M, Nanri T, Kawakita T, Horikawa K, Mitsuya H, Asou N.
  • Journal Title: Euro J Haematol 83 Pages: 499-501
  • Peer Reviewed
• [Journal Article] A JAK2-V617F activating mutation in addition to KIT and FLT3 mutations is associated with clinical outcome in patients with t(8;21) (q22;q22) acute myeloid leukemia. (2009)
  • Author(s): Iwanaga E, Nanri T, Matsuno N, Kawakita T, Mitsuya H, Asou N.
  • Journal Title: Haematologica 94 Pages: 433-435
  • Peer Reviewed
• [Journal Article] Micafungin-induced immune hemolysis attacks. (2009)
  • Author(s): Nanri T, Iwanaga E, Fujie S, Yamada Y, Horikawa K, Mitsuya H, Asou N.
  • Journal Title: Int J Hematol 89 Pages: 139-141
  • Peer Reviewed
• [Journal Article] Age-associated difference in gene expression of pediatric acute myelomonocytic lineage leukemia (FAB M4 and M5 subtypes) and its correlation with prognosis. (2009)
  • Author(s): Jo A, Tsukimoto I, Ishii E, Asou N, Mitani S, Shimada A, Igarashi T,, Hayashi Y, Ichikawa H.
  • Journal Title: Br J Haematol 144 Pages: 917-929
  • Peer Reviewed
• [Journal Article] Treatment of therapy-related acute myeloid leukemia occurring in elderly non-Hodgkin lymphoma patients with low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor. (2009)
  • Author(s): Tatetsu H, Matsuno F, Takatsu N, Miyake H, Hoshino K, Nosaka K, Horikawa K, Hata H, Mitsuya H, Asou N.
  • Journal Title: Leuk Res 33 Pages: 197-200
  • Peer Reviewed
• [Journal Article] Allogeneic bone marrow transplantation after 1-asparaginase-induced pancreatitis in a patient with acute lymphoblastic leukemia. (2008)
  • Author(s): Yamada Y, Ito K, Watanabe Y, Nosaka K, Horikawa K, Hidaka M, Kawano F, Sasaki Y, Mitsuya H, Asou N.
  • Journal Title: Leuk Res 32 Pages: 1944-1946
  • Peer Reviewed
• [Presentation] Clinical Features and Outcomes of Elderly Patients with Acute Promyelocytic Leukemia (APL)-the Japan Adult Leukemia Study Group APL97 Study (2010)
  • Author(s): Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, Tsuzuki M, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Yagasaki F, Kimura Y, Iwanaga M, Asou N, Naoe T, Ohno R.
  • Organizer: 52^<nd> ASH Annual Meeting
  • Place of Presentation: Orange Country Convention Center, Orlando, U.S.A
  • Year and Date: 20101204-20101207
• [Presentation] 高齢者急性骨髄性白血病に対するCAG療法における早期死亡例の解析 (2010)
  • Author(s): 鈴島仁、山崎浩、江藤健一郎、下村泰三、堀川健太郎、麻生範雄
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 20100924-20100926
• [Presentation] Over-expression of miR125 induces proliferation of multi-lineage hematopoietic cells and develops malignant tumors of lymphoid cells in vivo. (2010)
  • Author(s): Enomoto Y, Shimanuki M, Hatakeyama K, Taniwaki M, Asou N, Nakakuma H, Kitamura T, Sonoki T.
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 20100924-20100926
• [Presentation] APL治療後に併発したt(5;12)陽性慢性骨髄単球性白血病に対する少量イマチニブ療法 (2009)
  • Author(s): 麻生範雄、南里知子、岩永栄作、満屋裕明
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20091023-20091025
• [Presentation] カップ様(cup-like)の核形態を呈するHLA-DR陰性急性骨髄性白血病の臨床病理学的解析 (2009)
  • Author(s): 宮下要、本多絵美、崔日承、油布祐二、阿南建一、麻生範雄、鵜池直邦
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、、京都
  • Year and Date: 20091023-20091025
• [Presentation] Long-Term Follow-up of the Randomized JALSG AML 201 Study Comparing High Dose Ara-C Therapy with Conventional Consolidation Therapy in Adult Acute Myeloid Leukemia (AML). (2008)
  • Author(s): Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Miyamura K, Nishimura M, Miyazaki Y, Nishii K, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Organizer: 50^<th> ASH Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, U.S.A
  • Year and Date: 20081206-20081209
• [Presentation] Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myelogenous Leukemia (AML). Final Analysis of JALSG AML97 Study. (2008)
  • Author(s): Sakamaki H, Miyawaki S, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Takahashi M, Ogawa Y, Honda S, Ohno R.
  • Organizer: 50^<th> ASH Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, U.S.A
  • Year and Date: 20081206-20081209
• [Presentation] Updated Results of JALSG AML201 Study Comparing Intensified Daunorubicin with Idarubicin in Patients with De Novo Acute Myeloid Leukemia : Effect of Hematopoietic Stem Cell Transplantation. (2008)
  • Author(s): Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Miyamura K, Nishimura M, Miyazaki Y, Nishii K, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Honda S, Ohnishi K, Naoe T, Ohno R.
  • Organizer: 50^<th> ASH Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, U.S.A
  • Year and Date: 20081206-20081209
• [Presentation] ハイリスク骨髄異形成症候群に対する少量cytarabine, aclarubicinおよびG-CSF (CAG)療法 (2008)
  • Author(s): 和田奈緒子、鈴島仁、山崎浩、江藤健一郎、釘宮倫子、下村泰三、西村慎太郎、堀川健太郎、津田弘之、満屋裕明、麻生範雄
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20081010-20081012
• [Presentation] 高齢者急性骨髄性白血病に対する少量cytarabine, aclarubicinおよびG-CSF (CAG)療法 (2008)
  • Author(s): 鈴島仁、和田奈緒子、山崎浩、津田弘之、江藤健一郎、西村慎太郎、下村泰三、釘宮倫子、堀川健太郎、満屋裕明、麻生範雄
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20081010-20081012
• [Presentation] 急性骨髄性白血病におけるFLT3、CEBPA、NPM1、WT1遺伝子変異 (2008)
  • Author(s): 岩永栄作、南里知子、河北敏郎、松野直史、満屋裕明、麻生範雄
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20081010-20081012
• [Presentation] 急性前骨髄球性白血病における付加染色体異常の意義-JALSG APL97解析 (2008)
  • Author(s): 小野孝明、竹下明裕、岸本裕司、清井仁、岡田昌也、河合泰一、都築基弘、松田光弘、品川克至、小林透、大竹茂樹、西村美樹、高橋正知、矢ケ崎史治、大西一功、木村之彦、岩永正子、麻生範雄、直江知樹、大野竜三
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20081010-20081012
• [Presentation] 急性前骨髄球性白血病におけるRA症候群(JALSG APL97研究) (2008)
  • Author(s): 南里知子、麻生範雄、岸本裕司、清井仁、岡田昌也、河合泰一、都築基弘、松田光弘、品川克至、小林透、大竹茂樹、西村美樹、高橋正知、矢ケ崎史治、竹下明裕、木村之彦、岩永正子、直江知樹、大野竜三
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 20081010-20081012