Identification and functional analysis of gene aberrations in hematological malignancy with complex chromosomal abnormality using RNA-seq analysis

• Project/Area Number: 16K09860
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fujita Health University
• Principal Investigator: ABE AKIHIRO 藤田医科大学, 医学部, 客員准教授 (00432261)
• Co-Investigator(Kenkyū-buntansha): 恵美 宣彦 藤田医科大学, 医学部, 教授 (30185144) ; 山本 幸也 藤田医科大学, 医学部, 准教授 (90410703)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: RNA-seq / fusion gene / translocation / Leukemia / RUNX1 / G-CSF / TCF4 / MAML3 / ARID1B / EMID1 / 造血器腫瘍 / 融合遺伝子 / 複雑核型 / 白血病 / 染色体転座 / 癌 / 遺伝子 / ゲノム

Outline of Final Research Achievements

1. We have analyzed 48 cases of hematological malignancy using RNA-seq.
2. We have identified RUNX1-GRIK2as from relapsed/secondary acute myeloid leukemia (AML) with complex chromosomal abnormalities. This case was initially diagnosed as AML with inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. We found that several SNVs with high pathogenic scores were common in both initial and relapsed leukemia. Furthermore, the alteration of TP53 G245S occurred only at relapse.
3. We have also identified TM7SF3-VPS13B and VPS13B-RUNX1 from RUNX1-RUNX1T1-positive AML with t(8;12;21)(q22:p12;q22), ETV6-IAPP and ETV6-ABCC9 from two cases of AML with 12p abnormalities, and TCF4-MAML3 from blastic NK cell leukemia with complex chromosomal abnormalities involving t(4;18)(q31;q21).

Academic Significance and Societal Importance of the Research Achievements

本研究は、染色体核型からは推定困難な融合遺伝子を、網羅的次世代シークエンスによるRNA-seq解析を用いて同定し、複雑な染色体異常に関与する遺伝子異常を明らかにするとともに、得られた遺伝子異常の機能解析を進めるものである。今回同定した短縮型RUNX1がG-CSFへの反応性を高めること、再発時にTP53の変異が加わり複雑核型を示したことは、白血病発症機構を考える上で興味深い。また、複雑核型を有する症例は、治療困難な症例が多ため、そこに関与する遺伝子異常を明らかにすることは、新しい治療法を開発して行く上で役立つものと考える。

Research Products

• [Journal Article] Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells (2020)
  • Author(s): Inoue Chisato、Sobue Sayaka、Kawamoto Yoshiyuki、Nishizawa Yuji、Ichihara Masatoshi、Abe Akihiro、Hayakawa Fumihiko、Suzuki Motoshi、Nozawa Yoshinori、Murate Takahsi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 525 Issue: 4 Pages: 1074-1080
  • DOI: 10.1016/j.bbrc.2020.02.165
  • Peer Reviewed
• [Journal Article] Truncated RUNX1 generated from the fusion of RUNX1 to antisense GRIK2 via a cryptic chromosome translocation enhances sensitivity to granulocyte colony-stimulating factor (2020)
  • Author(s): Abe A, Yamamoto Y, Katsumi A, Yamamoto H, Okamoto A, Inaguma Y, Iriyama C, Tokuda M, Okamoto M, Emi N, Tomita A.
  • Journal Title: Cytogenetic and Genome Research Volume: - Issue: 5 Pages: 255-263
  • DOI: 10.1159/000508012
  • Peer Reviewed / Open Access
• [Journal Article] BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells. (2018)
  • Author(s): Inoue C, Sobue S, Aoyama Y, Mizutani N, Kawamoto Y, Nishizawa Y, Ichihara M, Abe A, Hayakawa F, Suzuki M, Nozawa Y, Murate T.
  • Journal Title: Biochem Biophys Rep. Volume: 15 Pages: 69-75
  • DOI: 10.1016/j.bbrep.2018.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Rearrangement of VPS13B, a causative gene of Cohen syndrome, in a case of RUNX1-RUNX1T1 leukemia with t(8;12;21). (2017)
  • Author(s): Abe A, Yamamoto Y, Katsumi A, Okamoto A, Tokuda M, Inaguma Y, Yamamoto K, Yanada M, Kanie T, Tomita A, Akatsuka Y, Okamoto M, Kameyama T, Mayeda A, Emi N.
  • Journal Title: Int J Hematol. Volume: - Issue: 2 Pages: 208-212
  • DOI: 10.1007/s12185-017-2387-x
  • Peer Reviewed / Open Access
• [Journal Article] Current treatment strategies for newly diagnosed and relapsed APL (2017)
  • Author(s): Emi N
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 10 Pages: 1872-1877
  • DOI: 10.11406/rinketsu.58.1872
  • NAID: 130006132669
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Autologous hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission: outcomes before and after the introduction of arsenic trioxide (2017)
  • Author(s): Yanada M, Yano S, Kanamori H, Gotoh M, Emi N, Watakabe K, Kurokawa M, Nishikawa A, Mori T, Tomita N, Murata M, Hashimoto H, Henzan H, Kanda Y, Sawa M, Kohno A, Atsuta Y, Ichinohe T, Takami A
  • Journal Title: Leuk Lymphoma Volume: 58 Issue: 5 Pages: 1061-1067
  • DOI: 10.1080/10428194.2016.1231406
  • Peer Reviewed
• [Journal Article] ETV6-LPXN fusion transcript generated by t(11;12)(q12.1;p13) in a patient with relapsing acute myeloid leukemia with NUP98-HOXA9. (2016)
  • Author(s): Abe A, Yamamoto Y, Iba S, Kanie T, Okamoto A, Tokuda M, Inaguma Y, Yanada M, Morishima S, Mizuta S, Akatsuka Y, Okamoto M, Kameyama T, Mayeda A, Emi N.
  • Journal Title: Genes, chromosomes & cancer Volume: 55(3) Issue: 3 Pages: 242-250
  • DOI: 10.1002/gcc.22327
  • Peer Reviewed
• [Journal Article] Transcriptional activation of platelet-derived growth factor receptor α and GS homeobox 2 resulting from E26 transformation-specific variant 6 translocation in a case of acute myeloid leukemia with t(4;12)(q12;p13). (2016)
  • Author(s): Abe A, Mizuta S, Okamoto A, Yamamoto Y, Kameyama T, Mayeda A, Emi N.
  • Journal Title: International journal of laboratory hematology Volume: 38(2) Issue: 2 Pages: 15-18
  • DOI: 10.1111/ijlh.12450
  • Peer Reviewed
• [Journal Article] Wnt signaling is associated with cell survival in the interaction between acute myeloid leukemia cells and stromal cells (2016)
  • Author(s): Niwa Y, Minami Y, Abe A, Hayakawa F, Yamada K, Naoe T
  • Journal Title: Leuk Lymphoma Volume: 57 Issue: 9 Pages: 2192-2194
  • DOI: 10.3109/10428194.2015.1124995
  • Peer Reviewed
• [Presentation] TCF4-MAML3融合遺伝子を認めたCD4+CD56+芽球性NK細胞白血病の１例 (2019)
  • Author(s): 安部明弘、山本幸也、山本秀行、徳田倍将、稲熊容子、岡本晃直、入山智沙子、冨田章裕、岡本昌隆、恵美宣彦
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] ETV6の再構成による異所性遺伝子発現を認めた急性骨髄性白血病の二症例 (2018)
  • Author(s): 安部明弘、山本幸也、岡本晃直、入山智沙子、徳田倍将、稲熊容子、蟹江匡治、冨田章裕、赤塚美樹、岡本昌隆、亀山俊樹、前田 明、恵美宣彦
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 再発急性骨髄性白血病において微小転座から複数のスプライシング産物を認めたRUNX1-GRIK2融合遺伝子 (2017)
  • Author(s): 安部明弘、山本幸也、岡本晃直、徳田倍将、稲熊容子、柳田正光、 蟹江匡治、冨田章裕、赤塚美樹、岡本昌隆、亀山俊樹、前田 明、恵美宣彦
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] ETV6転座によるPDGFRαとGSX2の高発現を認めたt(4;12)を有するAMLの一例 (2016)
  • Author(s): 安部明弘、水田秀一、山本幸也、岡本晃直、伊庭佐知子、徳田倍将、稲熊容子、柳田正光、 森島聡子、蟹江匡治、富田章裕、赤塚美樹、岡本昌隆、亀山俊樹、前田 明、恵美宣彦
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2016-10-13