Genetic abnormalities in acute myeloid leukemia at relapse

• Project/Area Number: 26461431
• 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
• Principal Investigator: Asou Norio 埼玉医科大学, 医学部, 教授 (50175171)
• Research Collaborator: MISHIMA Masayo ; FUJINAMI Miki
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 急性骨髄性白血病 / 再発 / 遺伝子変異 / サブクローン / 単一細胞PCR

Outline of Final Research Achievements

Gene mutations in patients with acute myeloid leukemia (AML) at initial diagnosis and relapse were examined. Mutations in the NPM1, FLT3, CEBPA, IDH1, IDH2, DNMT3A, WT1 and TP53 genes, that were frequently identified in AML patients, were mainly analyzed. Most AML patients with NPM1 mutation concomitantly had DNMT3A, FLT3, IDH1 or IDH2 mutation. Some gene mutations were withdrawn and others were acquired at relapse. In pair samples at diagnosis and relapse, it is analyzing whether an acquired gene mutation at relapse presents as a minor subclone at initial diagnosis by using whole exon sequencing and single cell PCR. These sequential molecular studies may yield valuable insights into the mechanism of leukemic recurrence.

Research Products

• [Int'l Joint Research] Barts Cancer Institute(United Kingdom)
• [Journal Article] Incidences and outcomes of therapy-related chronic myeloid leukemia in the era of tyrosine kinase inhibitors: Surveillance of the CML Cooperative Study Group. (2017)
  • Author(s): Iriyama N, Tokuhira M, Takaku T, Sato E, Ishikawa M, Nakazato T, Sugimoto KJ, Fujita H, Fujioka I, Hatta Y, Kizaki M, Komatsu N, Asou N, Kawaguchi T.
  • Journal Title: Leuk Res. Volume: 54 Pages: 55-58
  • DOI: 10.1016/j.leukres.2017.01.003
  • Peer Reviewed
• [Journal Article] Diagnostic performance of procalcitonin, presepsin, and C-reactive protein in patients with hematological malignancies. (2017)
  • Author(s): Ebihara Y, Kobayashi K, Ishida A, Maeda T, Takahashi N, Taji Y, Asou N, Ikebuchi K.
  • Journal Title: J Clin Lab Anal. Volume: in press Issue: 6
  • DOI: 10.1002/jcla.22147
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia. (2017)
  • Author(s): Togasaki E, Takeda J, Yoshida K, Shiozawa Y, Takeuchi M, Kiyoi H, Ohnishi K, Ohtake S, Asou N, Kobayashi Y, Miyazaki Y, Miyano S, Ogawa S, Matsumura I, Nakaseko C, Naoe T.
  • Journal Title: Blood Cancer J. Volume: 7 Issue: 4 Pages: 2017-2017
  • DOI: 10.1038/bcj.2017.36
  • Peer Reviewed / Open Access
• [Journal Article] Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to acute monoblastic leukemia at relapse. (2016)
  • Author(s): Higuchi Y, Tokunaga K, Watanabe Y, Kawakita T, Harada N, Yamaguchi S, Nosaka K, Mitsuya H, Asou N.
  • Journal Title: Cancer Genet Volume: 209 Issue: 6 Pages: 267-271
  • DOI: 10.1016/j.cancergen.2016.05.070
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission (2016)
  • Author(s): Yanada, M., Kanda, J., Ohtake, S., Fukuda, T., Sakamaki, H., Miyamura, K., Miyawaki, S., Uchida, N., Maeda, T., Nagamura-Inoue, T., Asou, N., Morishima, Y., Atsuta, Y., Miyazaki, Y., Kimura, F., Kobayashi, Y., Takami, A., Naoe, T. and Kanda, Y
  • Journal Title: Eur J Haematol Volume: NA Issue: 3 Pages: 278-287
  • DOI: 10.1111/ejh.12723
  • Peer Reviewed
• [Journal Article] Proposal of criteria for dyserythropoiesis in the diagnosis of myelodysplastic syndromes. (2016)
  • Author(s): Kawai N, Matsuda A, Jinnai I, Ichimura T, Kayano H, Okamura D, Ishikawa M, Maeda T, Hata T, Miyazaki Y, Asou N, Bessho M, Tomonaga M.
  • Journal Title: Int J Hematol Volume: 103 Issue: 2 Pages: 227-233
  • DOI: 10.1007/s12185-015-1916-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. (2016)
  • Author(s): Ogura M, Imaizumi Y, Uike N, Asou N, Utsunomiya A, Uchida T, Aoki T, Tsukasaki K, Taguchi J, Choi I, Maruyama D, Nosaka K, Chen N, Midorikawa S, Ohtsu T, Tobinai K.
  • Journal Title: Lancet Haematol Volume: 3 Issue: 3 Pages: e107-e118
  • DOI: 10.1016/s2352-3026(15)00284-7
  • Peer Reviewed
• [Journal Article] Disease evolution and outcomes in familial AML with germline CEBPA mutations. (2015)
  • Author(s): Tawana K, Wang J, Renneville A, Hills R, Loveday C, Savic A, Van Delft FW, Treleaven J, Georgiades P, Uglow E, Asou N, Uike N, Debeljak M, Jazbec J, Ancliff P, Gale R, Thomas X, Mialou V, Döhner K, Bullinger L, Preudhomme C, Chelala C, Cavenagh J, Fitzgibbon J, et al.
  • Journal Title: Blood Volume: 126 Issue: 10 Pages: 1214-1223
  • DOI: 10.1182/blood-2015-05-647172
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients (2014)
  • Author(s): Kihara R, S. Ogawa, S. (32/33) Naoe, T.
  • Journal Title: Leukemia Volume: inpress Issue: 8 Pages: 1586-95
  • DOI: 10.1038/leu.2014.55
  • Peer Reviewed
• [Journal Article] Hematologic improvements in a myelodysplastic syndromes with myelofibrosis (MDS-F) patient treated with azacitidine. (2014)
  • Author(s): Okamura D, Matsuda A, Ishikawa M, Maeda T, Tanae K, Kohri M, Takahashi N, Kawai N, Asou N, Bessho M.
  • Journal Title: Leuk Res Rep Volume: 3 Issue: 1 Pages: 24-27
  • DOI: 10.1016/j.lrr.2014.03.002
  • Peer Reviewed
• [Journal Article] Tamibarotene As Maintenance Therapy for Acute Promyelocytic Leukemia: Results From a Randomized Controlled Trial. (2014)
  • Author(s): Shinagawa K, Yanada M, Sakura T, Ueda Y, Sawa M, Miyatake J, Dobashi N, Kojima M, Hatta Y, Emi N, Tamaki S, Gomyo H, Yamazaki E, Fujimaki K, Asou N, Matsuo K, Ohtake S, Miyazaki Y, Ohnishi K, Kobayashi Y, Naoe T.
  • Journal Title: J Clin Oncol. Volume: 32 Issue: 33 Pages: 3729-3735
  • DOI: 10.1200/jco.2013.53.3570
  • Peer Reviewed
• [Presentation] APL harboring the PML-RARA fusion gene detected by RT-PCR, which was negative by FISH analysis. (2016)
  • Author(s): 佐伯豪士、岡村大輔、石川真穂、前田智也、川井信孝、松田晃、麻生範雄
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2016-10-14
• [Presentation] 3’UTR methylation of the CEBPA gene in acute myeloid leukemia. (2016)
  • Author(s): 木村由起子、徳永賢治、松野直史、麻生範雄、川口辰哉、岩永栄作
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2016-10-14
• [Presentation] AMLの層別化治療 (2016)
  • Author(s): 麻生範雄
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] Landscape of MDS genomes as revealed by whole genome sequencing. (2016)
  • Author(s): 南谷泰仁、吉田健一、片岡圭亮、永田安伸、吉里哲一、木口亨、土橋史明、臼杵憲祐、直江知樹、清井仁、千葉滋、麻生範雄、宮崎泰司、田中洋子、千葉健一、白石友一、宮野悟、小川誠司
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2016-10-13
• [Presentation] Genetic Predispositions to Myeloid Neoplasms Caused By Germline DDX41 Mutations. (2015)
  • Author(s): Takeda J, Yoshida K, Makishima H, Yoshizato T, Shiozawa Y, Shiraishi Y, Okuno Y, Kon A, Nagata Y, Kataoka K, Chiba K, Tanaka H, Sanada M, Sakata-Yanagimoto M, Obara N, Nakamaki T, Ishiyama K, Haigaishi A, Chiba S, Mori H, Asou N, Kiyoi H, Miyazaki Y, Naoe T, Kubo M, Polprasert C, Maciejewski JP, Ogawa S, et al.
  • Organizer: 57th ASH Annual Meeting & Exposition
  • Place of Presentation: Orange Country Convention Center, Orlando, U.S.A
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] WT1 mRNA levels in peripheral blood may be a predictive marker on response to azacitidine in MDS. (2015)
  • Author(s): Maeda T, Matsuda A, Okamura D, Ishakawa M, Kohri M, Takahashi N, Niitsu N, Kawai N, Asou N, Bessho M.
  • 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、金沢市、石川県
  • Year and Date: 2015-10-16
• [Presentation] Succesful treatment with dasatinib and chemotherapy for an ALL harboring a rare e14a3 BCR-ABL. (2015)
  • Author(s): Ishikawa M, Okamura D, Maeda T, Kawai N, Matsuda A, Minauchi K, Imai K, Asou N.
  • 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、金沢市、石川県
  • Year and Date: 2015-10-16
• [Presentation] Relatonship between morphological features and gene mutations in de novo AML. (2015)
  • Author(s): Kamijo R, Itonaga H, Kihara R, Nagata Y, Hata T, Asou N, Ohatake S, Ogawa S, Naoe T, Kiyoi H, Miyazaki Y.
  • 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、金沢市、石川県
  • Year and Date: 2015-10-16
• [Presentation] Predicitive impact of baseline WT1 mRNA expression level in peripheral blood on response to azacitidine in MDS patients. (2015)
  • Author(s): Maeda T, Matsuda A, Okamura D, Ishikawa M, Kohri M, Takahashi N, Niitsu N, Kawai N, Asou N, Bessho M.
  • Organizer: The 6th JSH International Symposium 2015
  • Place of Presentation: 軽井沢プリンスホテルウエスト、軽井沢町、長野県
  • Year and Date: 2015-05-22
  • Int'l Joint Research
• [Presentation] Morphologic analysis to create suitable criteris for dyserythropoiesis in the diagnosis of myelodysplastic syndromes. (2015)
  • Author(s): Kawai N, Matsuda A, Jinnai I, Ichimura T, Kayano H, Okamura D, Ishikawa M, Maeda T, Hata T, Miyazaki Y, Asou N, Bessho M, Tomonaga M.
  • Organizer: The 6th JSH International Symposium 2015
  • Place of Presentation: 軽井沢プリンスホテルウエスト、軽井沢町、長野県
  • Year and Date: 2015-05-22
  • Int'l Joint Research
• [Presentation] Prognostic Impact of Chromosomal Variation in Patients with Acute Promyelocytic Leukemia (APL); Analysis of 775 Cases Enrolled in the Japan Adult Leukemia Study Group APL Studies. (2014)
  • Author(s): Adachi M, Takeshita A, Taki T, Ohtake S, Shinagawa K, Kiyoi H, Matsuda M, Takahashi M, Emi N, Kobayashi Y, Miyamura K, Fujita H, Sakura T, Iwanaga M, Usui N, Miyawaki S, Asou N, Ohnishi K, Miyazaki Y, Naoe T.
  • Organizer: 56th ASH Annual Meeting and Exposition.
  • Place of Presentation: Moscone Center, San Francisco, CA, U.S.A.
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Alterations of TP53, CREBBP and EED genes in adult patients with acute lymphoblastic leukemia. (2014)
  • Author(s): Tokunaga K, Yamaguchi S, Shimomura T, Suzushima H, Mitsuya H, Asou N.
  • Organizer: The 76th Annual Meeting of the Japanese Society of Hematology.
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2014-10-31 – 2014-11-02