Development of novel therapy for leukemia targeting metabolism-dependent protein modification

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17833
• 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: Kumamoto University
• Principal Investigator: Morishima Tatsuya 熊本大学, 国際先端医学研究機構, 特任助教 (40421375)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 白血病 / アセチル化 / LMO2 / NAD+ / NAMPT / Sirtuin / 代謝

Outline of Final Research Achievements

Hematopoietic transcription factor LMO2 plays an essential role in early hematopoiesis and is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL) patients. In this study, we studied whether NAMPT- or SIRT2-specific inhibitors, which inhibit LMO2 protein activation through regulation of acetylation, have a therapeutic effect on T-ALL.
We revealed that NAMPT- or SIRT2-specific inhibitors could suppress proliferation of T-ALL cell lines and T-ALL patient cells which express LMO2 protein in LMO2 acetylation dependent manner. We also identified genes whose expression is regulated by LMO2 acetylation using RNA sequencing analysis.

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

本研究によりLMO2タンパク質がT-ALLにおいて活性化され、腫瘍化を引き起こす分子メカニズムが明らかとなり、NAMPT・SIRT2経路の特異的阻害薬によりT-ALLを治療できる可能性が示された。また我々はLMO2タンパク質のアセチル化部位も同定しており、本研究で得られた知見を応用することにより同部位の脱アセチル化を阻害する低分子化合物を用いたより特異性の高い分子標的療法の開発につながることが期待される。