Elucidation of pathogenesis and novel therapeutics for refractory leukemias

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H04052
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration 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): 2018-04-01 – 2021-03-31
• Keywords: 急性骨髄性白血病

Outline of Final Research Achievements

The pathogenesis of EVI1-positive leukemia, known as refractory acute myeloid leukemia (AML), has been elucidated using mouse models and genetically modified cell lines. Specifically, we extracted molecules that contribute to the pathogenesis of the normal, preleukemic, and AML states, and clarified some of the functions of EVI1, such as co-factors, histone modifications, enhancers, transcriptional regulation, and metabolic regulation, that are involved in the pathogenesis of refractory AML.
The functional significance of EVI1 in AML was elucidated by NGS analysis using DNMT3A mutation repair strains.
Using human AML specimens, we identified BCOR and MAP4K2 as novel mutations that confer resistance to treatment, and elucidated part of the mechanism of resistance to treatment.

Free Research Field

血液・腫瘍病態学

Academic Significance and Societal Importance of the Research Achievements

難治性白血病の治療開発を推進するためには、網羅的解析技術により遺伝子異常を同定することに加え、エピジェネティクス、代謝、骨髄造血環境など、難治性病態を形成する異常の相互作用を、in vitro、in vivoの適切なモデルを活用して明らかにし、治療標的化する必要がある。今回我々はEVI1陽性型白血病の発症・難治化機構の解明と、白血病特異的な標的・協調因子の探索、エピジェネティクス異常に基づく白血病モデルマウスを用いた解析、治療抵抗性をもたらす新規遺伝子変異の同定とその機能解析を行い、難治性白血病の病態の一端を明らかにした。
これらの結果より、難治性白血病の新規治療開発の基盤モデルを確立した。