Prognostic implications of the genetic abnormalities in adult patients with acute lymphoblastic leukemia

• Project/Area Number: 23591396
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Saitama Medical University (2013); Kumamoto University (2011-2012)
• Principal Investigator: ASOU Norio 埼玉医科大学, 医学部, 教授 (50175171)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 急性リンパ性白血病 / IKZF1遺伝子 / エピゲノム / EED遺伝子 / CREBBP遺伝子 / TP53遺伝子 / フィラデルフィア染色体 / 予後予測 / ヒストン / H3K27 / CREBBP / EED / TP53 / BCR-ABL / ALL / CBP / IKZF1 / PAX5 / JAK2 / PRC2 / EZH2

Research Abstract

The aim in this study is to establish a prognostic scoring system based on the genetic abnormalities in adult patients with acute lymphoblastic leukemia (ALL). Recently, comprehensive gene analysis in pediatric ALL brought new genetic abnormalities such as IKZF1 and CREBBP. In this study, alterations in the IKZF1 gene were frequently detected in adult ALL (53%) compared to that of pediatric ALL. Although no mutation in the epigenetic modifiers such as UTX, SUZ12, RPD3 or EZH2 was found, mutations in the EED and CREBBP were detected in adult ALL. 5-year relapse-free survival in patients without mutation, with one mutation and with two or more mutations in the IKZF1, EED, CREBBP or TP53 genes was 47%, 22% and 0%, respectively, indicating that these gene mutations confer a poor clinical outcome in adult Philadelphia chromosome-negative ALL.

Research Products

• [Journal Article] IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation. (2014)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Journal Title: Eur J Haematol Volume: in press Issue: 6 Pages: 471-477
  • DOI: 10.1111/ejh.12271
  • Peer Reviewed
• [Journal Article] Normal karyotype acute myeloid leukemia with the CD7+ CD15+ CD34+ HLA-DR + immunophenotype is a clinically distinct entity with a favorable outcome. (2014)
  • Author(s): Iriyama N, Asou N, Miyazaki Y, Yamaguchi S, Sato S, Sakura T, Maeda T, Handa H, Takahashi M, Ohtake S, Hatta Y, Sakamaki H, Honda S, Taki T, Taniwaki M, Miyawaki S, Ohnishi K, Kobayashi Y, Naoe T.
  • Journal Title: Ann Hematol Volume: in press Issue: 6 Pages: 957-963
  • DOI: 10.1007/s00277-014-2013-4
  • Peer Reviewed
• [Journal Article] Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts. (2014)
  • Author(s): Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, Emi N, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Kimura Y, Iwanaga M, Asou N, Naoe T; Japan Adult Leukemia Study Group.
  • Journal Title: Cancer Sci Volume: 105 Issue: 1 Pages: 97-104
  • DOI: 10.1111/cas.12319
  • Peer Reviewed / Open Access
• [Journal Article] Akt-Induced Phosphorylation of N-CoR at Serine 1450 Contributes to Its Misfolded Conformational Dependent Loss (MCDL) in Acute Myeloid Leukemia of the M5 Subtype. (2013)
  • Author(s): Nin DS, Ali AB, Okumura K, Asou N, Chen CS, Chng WJ, Khan M.
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e70891-e70891
  • DOI: 10.1371/journal.pone.0070891
  • Peer Reviewed
• [Journal Article] Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97. (2013)
  • Author(s): Fujita H, Asou N, Iwanaga M, Hyo R, Nomura S, Kiyoi H, Okada M, Inaguma Y, Matsuda M, Yamauchi T, Ohtake S, Izumi T, Nakaseko C, Ishigatsubo Y, Shinagawa K, Takeshita A, Miyazaki Y, Ohnishi K, Miyawaki S, Naoe T; Japan Adult Leukemia Study Group.
  • Journal Title: Cancer Sci Volume: 104 Issue: 10 Pages: 1339-1345
  • DOI: 10.1111/cas.12230
  • Peer Reviewed
• [Journal Article] High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia. (2013)
  • Author(s): Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Journal Title: Euro J Haematol Volume: 91 Issue: 3 Pages: 201-208
  • DOI: 10.1111/ejh.12155
  • Peer Reviewed
• [Journal Article] The demarcation between younger and older acute myeloid leukemia patients. (2013)
  • Author(s): Yanada M, Ohtake S, Miyawaki S, Sakamaki H, Sakura T, Maeda T, Miyamura K, Asou N, Oh I, Miyatake J, Kanbayashi H, Takeuchi J, Takahashi M, Dobashi N, Kiyoi H, Miyazaki Y, Emi N, Kobayashi Y, Ohno R, Naoe T.
  • Journal Title: Cancer Volume: 119 Issue: 18 Pages: 3326-3333
  • DOI: 10.1002/cncr.28212
  • Peer Reviewed
• [Journal Article] AMLの分子病態と診断 (2012)
  • Author(s): 麻生範雄
  • Journal Title: 臨床血液 Volume: 53, (PMID : 23037727) Pages: 1549-1559
  • NAID: 10031123843
• [Journal Article] Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia (2012)
  • Author(s): Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, Tsuzuki M, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Kimura Y, Iwanaga M, Asou N, Naoe T
  • Journal Title: Cancer Sci. Volume: 103 Issue: 11 Pages: 174-1978
  • DOI: 10.1111/j.1349-7006.2012.02390.x
  • Peer Reviewed
• [Journal Article] AMLの分子病態と診断 (2012)
  • Author(s): Asou N
  • Journal Title: 臨床血液 Volume: 53 Pages: 1549-1559
  • NAID: 10031123843
• [Journal Article] Em/miR-125b transgenic mice develop lethal B-cell malignancies (2011)
  • Author(s): Enomoto, Y
  • Journal Title: Leukemia Volume: 25 Issue: 12 Pages: 1849-1856
  • DOI: 10.1038/leu.2011.166
  • Peer Reviewed
• [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 Volume: 117 Issue: 8 Pages: 2366-2372
  • DOI: 10.1182/blood-2010-07-295279
  • 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 Volume: 117 Issue: 8 Pages: 2358-2365
  • DOI: 10.1182/blood-2010-03-273243
  • 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 Volume: 38, (PMID : 21109922) Pages: 25-31
  • Peer Reviewed
• [Journal Article] Impact of additional chromosomal abnormalities in patients with acute promyelocytic leukemia : 10-year results of the Japan Adult Leukemia Study Group APL97 study (2011)
  • Author(s): Ono T, Takeshita A, et al
  • Journal Title: Haematologica Volume: 96(1) Issue: 1 Pages: 174-6
  • DOI: 10.3324/haematol.2010.030205
  • 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 Volume: 38 Issue: 1 Pages: 25-31
  • DOI: 10.3892/ijo_00000820
  • Peer Reviewed
• [Presentation] Normal Karyotype-Acute Myeloid Leukemia With The CD4- CD7+ CD15+ CD34+ Immunophenotype Is a Clinically Distinct Entity With a Favorable Outcome (2013)
  • Author(s): Iriyama N, Asou N, Sakura T, Maeda T, Handa H, Takahashi M, Ohtake S, Hatta Y, Sakamaki H, Honda S, Miyazaki Y, Miyawaki S, Taniwaki M, Taki T, Yamaguchi S, Satou S and Naoe T
  • Organizer: 55^<th> ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2013-12-08
• [Presentation] Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia (2013)
  • Author(s): Tokunaga K, Yamaguchi S, Shimomura T, Suzushima H, Okuno Y, Mitsuya H, and Asou N
  • Organizer: 55^<th> ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, U.S.A
  • Year and Date: 2013-12-07
• [Presentation] Mutations of the modifiers of H3K27 (CREBBP and EED) in adult acute lymphoblastic leukemia (2013)
  • Author(s): Tokunaga K, Yamaguchi S, Shimomura T, Suzushima H, Mitsuya H, Asou N
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
  • Year and Date: 2013-10-11
• [Presentation] Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to AMoL at relapse (2013)
  • Author(s): Higuchi Y, Watanabe Y, Tokunaga K, Nosaka K, Mitsuya H, Asou N
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
  • Year and Date: 2013-10-11
• [Presentation] IDH1 and IDH2 mutations confer adverse prognosis in acute myeloid leukemia with wild-type NPM1 (2013)
  • Author(s): Yamaguchi, S, Iwanaga E, Tokunaga K, Nanri T, Shmomura T, Suzushima H, Nitsuya H, Asou N
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
  • Year and Date: 2013-10-11
• [Presentation] Clonal heterogeneity and evolution of acute myeloid leukemia during disease progression (2013)
  • Author(s): Kihara R, Hoshino H, Suzuki K, Chen F, Kato T, Miyawaki S, Asou N, Taki T, Taniwaki M, Naoe T, Kiyoi H
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
  • Year and Date: 2013-10-11
• [Presentation] Crebbp HAT domain mutations are frequently detected in adult acute lymphoblastic leukemia (2012)
  • Author(s): Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H, Mitsuya H, and Asou N
  • Organizer: 54^<th> ASH Annual Meeting
  • Place of Presentation: Atlanta
• [Presentation] Prognostic impact and concurrent genetic alterations of CEBPA double mutations in adults with cytogenetically intermediate-risk acute myeloid leukemia (2012)
  • Author(s): Yamaguchi S, Tokunaga K, Iwanaga E, Nanri T, Shimomura T, Suzushima H, Mitsuya H, and Asou N
  • Organizer: 54^<th> ASH Annual Meeting
  • Place of Presentation: Atlanta
• [Presentation] AMLの分子病態と診断 (2012)
  • Author(s): 麻生範雄
  • Organizer: 第74回日本血液学会学術総会
  • Place of Presentation: Kyoto
• [Presentation] IKZF1 alterations in adults with B-cell acute lymphoblastic leukemia (B-ALL) (2012)
  • Author(s): Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H, Mitsuya H, and Asou N
  • Organizer: 第74回日本血液学会学術総会
  • Place of Presentation: Kyoto
• [Presentation] Prognostic impact of FLT3, CEBPA, NPM1, IDH1 and IDH2 gene mutations in patients with AML (2012)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N
  • Organizer: 第74回日本血液学会学術総会
  • Place of Presentation: Kyoto
• [Presentation] Prognostic impact of FLT3, CEBPA, NPM1, IDH1 and IDH2 gene mutations in patients with AML. (2012)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Organizer: 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 国立京都国際会館、京都
• [Presentation] IKZF1 alterations in adults with B-cell acute lymphoblastic leukemia (B-ALL) (2012)
  • Author(s): Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Organizer: 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 国立京都国際会館、京都
• [Presentation] AMLの分子病態と診断 (2012)
  • Author(s): 麻生範雄
  • Organizer: 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 国立京都国際会館、京都
  • Invited
• [Presentation] Prognostic Impact and Concurrent Genetic Alterations of CEBPA Double Mutations in Adults with Cytogenetically Intermediate-Risk Acute Myeloid Leukemia. (2012)
  • Author(s): Shunichiro Yamaguchi, Kenji Tokunaga, Eisaku Iwanaga, Tomoko Nanri, Taizo Shimomura, Hitoshi Suzushima, Hiroaki Mitsuya and Norio Asou
  • Organizer: 54th ASH Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia. (2012)
  • Author(s): Kenji Tokunaga, Shunichiro Yamaguchi, Eisaku Iwanaga, Tomoko Nanri, Taizo Shimomura, Hitoshi Suzushima, Mitsuya Hiroaki, and Norio Asou.
  • Organizer: 54th ASH Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Role of Hematopoietic Stem Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated with All-Trans-Retinoic Acid : A Retrospective Analysis of the Japan Adult Leukemia Study Group (JALSG) APL97 Study (2011)
  • Author(s): Fujita H, Asou N, Iwanaga M, Hyo R, Nomura S, Kiyoi H, Okada M, Tsuzuki M, Matsuda M, Yamauchi T, Ohtake S, Izumi T, Nakaseko C, Mitani K, Shinagawa K, Takeshita A, Miyazaki Y, Ohnishi K, Miyawaki S, and Naoe T
  • Organizer: 53^<rd> ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A
• [Presentation] Clinical Features and Prognostic Impact of CD56 Expression in Acute Promyelocytic Leukemia : Long Term Follow up Data From the Japan Adult Leukemia Study Group (JALSG) APL97 (2011)
  • Author(s): Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, Tsuzuki M, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Yagasaki F, Kimura Y, Fujita H, Iwanaga M, Asou N, Ohnishi K, and Naoe T
  • Organizer: 53^<rd> ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A
• [Presentation] IDH2 mutations have an unfavorable impact in elderly patients with acute myeloid leukemia (2011)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Suzushima H, Shimomura T, Mitsuya H, and Asou N
  • Organizer: 53^<rd> ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A
• [Presentation] IDH1 and IDH2 mutations in Japanese patients with acute myeloid leukemia (2011)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Shimomura T, Suzushima H, Mitsuya H, Asou N
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [Presentation] IKZF1 deletions in adult B-cell acute lymphoblastic leukemia (2011)
  • Author(s): Tokunaga K
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [Presentation] IKZF1 deletions in adult B-cell acute lymphoblastic leukemia. (2011)
  • Author(s): Tokunaga K.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [Presentation] IDH2 mutations have an unfavorable impact in elderly patients with acute myeloid leukemia. (2011)
  • Author(s): Yamaguchi S, Iwanaga E, Tokunaga K, Nanri T, Suzushima H, Shimomura T, Mitsuya H, Asou N.
  • Organizer: 53rd ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A.
• [Presentation] Clinical Features and Prognostic Impact of CD56 Expression in Acute Promyelocytic Leukemia: Long Term Follow up Data From the Japan Adult Leukemia Study Group(JALSG) APL97 (2011)
  • Author(s): Ono T, Takeshita A, Asou N, Ohnishi K, Naoe T, et al.
  • Organizer: 53rd ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A.
• [Presentation] Role of Hematopoietic Stem Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated with All-Trans-Retinoic Acid: A Retrospective Analysis of the Japan Adult Leukemia Study Group (JALSG) APL97 Study (2011)
  • Author(s): Fujita H, Asou N, Miyawaki S, Naoe T, et al.
  • Organizer: 53rd ASH Annual Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, CA, U.S.A.
• [Presentation] Clonal heterogeneity and evolution of acute myeloid leukemia during disease progression.
  • Author(s): Kihara R, Hoshino H, Suzuki K, Chen F, Kato T, Miyawaki S, Asou N, Taki T, Taniwaki M, Naoe T, Kiyoi H.
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
• [Presentation] IDH1 and IDH2 mutations confer adverse prognosis in acute myeloid leukemia with wild-type NPM1.
  • Author(s): Yamaguchi, S, Iwanaga E, Tokunaga K, Nanri T, Shmomura T, Suzushima H, Nitsuya H, Asou N.
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
• [Presentation] Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to AMoL at relapse.
  • Author(s): Higuchi Y, Watanabe Y, Tokunaga K, Nosaka K, Mitsuya H, Asou N.
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
• [Presentation] Mutations of the modifiers of H3K27 (CREBBP and EED) in adult acute lymphoblastic leukemia.
  • Author(s): Tokunaga K, Yamaguchi S, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Organizer: 第75回日本血液学会学術総会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館、札幌市教育文化会館、札幌
• [Presentation] Normal Karyotype-Acute Myeloid Leukemia With The CD4- CD7+ CD15+ CD34+ Immunophenotype Is a Clinically Distinct Entity With a Favorable Outcome.
  • Author(s): Iriyama N, Asou N, Sakura T, Maeda T, Handa H, Takahashi M, Ohtake S, Hatta Y, Sakamaki H, Honda S, Miyazaki Y, Miyawaki S, Taniwaki M, Taki T, Yamaguchi S, Satou S and Naoe T.
  • Organizer: 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, U.S.A.
• [Presentation] Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia.
  • Author(s): Tokunaga K, Yamaguchi S, Shimomura T, Suzushima H, Okuno Y, Mitsuya H, and Asou N.
  • Organizer: 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, U.S.A.