Development of Novel Therapies for Refractory Leukemia Based on Mechanistic Insights

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04805
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Kurokawa Mineo 東京大学, 医学部附属病院, 教授 (80312320)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: 難治性白血病 / EVI1 / 腫瘍免疫

Outline of Final Research Achievements

We conducted a detailed analysis of the significance of the CCND1 and IFN-γ pathways in a mouse model of difficult-to-treat leukemia with high expression of EVI1. We found that inhibition of CCND1 suppresses proliferation in EVI1-high leukemia, with a more pronounced effect observed in vivo compared to in vitro. Inhibition of CCND1 led to decreased expression of genes involved in chemokine production and interferon response, as well as decreased expression of PD-L1 in EVI1-high leukemia cells. Mice with EVI1-high leukemia treated with inhibitors of CCND1, interferon-gamma receptor, and the downstream signaling hub molecule STAT1 showed delayed onset of the disease. Infiltrating T cells in the spleens of these mice showed reduced exhaustion markers. Combined with the detailed analysis on the related chemokine, our observation indicate that the CCND1-IFN-γ-STAT1 axis contributes to the refractory nature of EVI1-high leukemia via T cell exhaustion.

Free Research Field

血液内科

Academic Significance and Societal Importance of the Research Achievements

我々は CCND1-IFN-γ-STAT1軸の異常 が腫瘍免疫の異常を誘導しており、これがEVI1高発現白血病の治療標的となりうることを見出した。今後はIFN-γ、IFN-γ受容体、STAT1などの欠失マウスを用いて、EVI1高発現白血病をはじめとする難治性白血病における同様の腫瘍免疫の異常が広く急性骨髄性白血病の治療標的となるか検証を行う。本治療戦略が有効な白血病サブタイプの同定を行い、急性骨髄性白血病の新たな治療法の確立を目指す。本研究成果は将来的に、予後不良の難治生白血病患者に対する全く新しい治療法の開発のための基礎的知見の集積に大きく貢献するものである。