Targeting the haematopoietic stem cell programme to understand the molecular basis of refractory acute myeloid leukaemia.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03708
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: MASAMOTO YOSUKE 東京大学, 医学部附属病院, 准教授 (30706974)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 急性骨髄性白血病 / 白血病幹細胞

Outline of Final Research Achievements

In the EVI1-GFP knock-in retrovirally induced MLL-ENL murine AML model, HSC-like and GMP-like AML cells were sorted by GFP expression and compared for gene expression pattern. The HSC-like AML cells induce refractory AML despite low leukemia stem cell frequency. The HSC-like AML cells were characterized by enrichment of the NF-κB pathway, chemotherapy resistance-related gene cluster, and elevated chemokine expression, consistent with the phenotype of HSC-like AML cells. The EVI1-high AML model with HSC-like expression patterns also shared the same transcriptional profile as HSC-like AML cells: the immune-related pathways, including chemokines and IFN-γ pathway, which were regulated by cyclin D1. We also demonstrated that the genetic modification of Cyclin D1, chemokine and IFN-γ pathway can suppress AML development.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

代表的造血器腫瘍であるAMLの難治性病態を解明するため、AML幹細胞の中でも特に難治性病態に関連するHSC様AML細胞の性質の解析を行った。HSC様AML細胞は幹細胞活性の高さとは関係なく、既知の難治性関連遺伝子群の発現と関連しており、さらに面白いことに、免疫関係の遺伝子発現と関連していた。複数のAMLモデルを用いることにより、cyclin D1, ケモカイン、IFN-γ経路などがHSC様AML細胞を特徴づけることを明らかにした。またこれらの経路がHSC様AML細胞の脆弱性を構成し、治療標的になりうる可能性を提示した。