Investigating molecular basis of chemoresistance using a novel leukemia cell line harboring high-risk chromosome abnormalities

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08400
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Yokohama City University
• Principal Investigator: KUNIMOTO Hiroyoshi 横浜市立大学, 医学部, 助教 (80464923)
• Co-Investigator(Kenkyū-buntansha): 中島 秀明 横浜市立大学, 医学研究科, 教授 (30217723)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: YCU-AML1 / OCI-AML20 / EZH2 / apoptosis / GADD45g / p38 / p53

Outline of Final Research Achievements

Drug screen assay revealed that multiple EZH2 inhibitors show pharmacological activity against YCU-AML1 and OCI-AML20 cells, two human AML cell lines harboring both inv(3)/t(3;3) and -7. In vitro culture with EZH2 inhibitors significantly suppressed cell growth of YCU-AML1 and OCI-AML20 cells. In addition, EZH2 inhibition efficiently induced apoptosis in these AML cell lines. In order to seek the exact molecular basis of EZH2 inhibitor-mediated apoptosis induction in YCU-AML1 and OCI-AML20 cells, we performed RNA-seq and CUT&Tag-seq. These omics data revealed that GADD45g-p38-p53 axis is activated upon EZH2 inhibition in these cells and that epigenetic silencing of GADD45g-p38-p53 axis is a major molecular mechanism by which high-risk MDS/AML cells with inv(3)/t(3;3) and -7 evade apoptosis cell death.

Free Research Field

血液・腫瘍内科

Academic Significance and Societal Importance of the Research Achievements

臨床的に予後不良なinv(3)/t(3;3)と-7の両者を有するMDS/AML細胞の細胞増殖を抑制し効率的にアポトーシスを誘導する分子標的薬としてEZH2阻害剤を見出すことに成功した。in vitro培養系のみならずin vivo生体モデルでもEZH2阻害剤はYCU-AML1によるヒト白血病発症能を抑制することも確認した。その分子基盤として、GADD45g-p38-p53経路の活性化がEZH2阻害によるアポトーシス誘導に必須であることを明らかにし、定常状態における本経路の抑制がinv(3)/t(3;3)と-7を有する白血病のアポトーシス回避に重要であることを明らかにした。