The role of proteasome in acute myeloid leukemia

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16110
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• 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, 講師 (30706974)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 急性骨髄性白血病 / プロテアソーム

Outline of Final Research Achievements

Acute myeloid leukemia (AML) is a refractory hematopoietic tumor, of which novel therapeutic target are expected to be discovered. Using a mouse model, we investigated the regulation of proteasome activity in AML and its significance as a therapeutic target. Proteasome activity was increased in AML cells, especially in the cell fraction with high proliferative activity, as compared to normal cells. Exposure to chemotherapeutic agents used for AML treatment suppressed proteasome activity and activated autophagy. AML cells with reduced proteasome activity acquired resistance to chemotherapeutic agents, whereas AML cells with increased proteasome activity became more sensitive to these drugs. It was suggested that inhibition of autophagy would further increase sensitivity and could be a therapeutic target.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

急性骨髄性白血病(AML)細胞では選択的なタンパク分解系であるプロテアソーム活性が亢進しているものの、抗がん剤などのストレスに暴露されるとプロテアソーム活性を抑制してオートファジーを活性化することでそれに対して抵抗性を獲得することが明らかになった。またオートファジーとプロテアソームの活性を同時に阻害してこの機序を阻害することでAML細胞の化学療法感受性が著しく亢進し、AMLの新たな治療標的になりうる可能性が示唆された。