Energy metabolism of childhood refractory leukemia

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17367
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: University of Miyazaki
• Principal Investigator: Mariko Kinoshita 宮崎大学, 医学部, 助教 (40740345)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 白血病 / がん代謝

Outline of Final Research Achievements

We analyzed bone marrow samples in patients with leukemia, and identified its higher dependence on oxidative phosphorylation (OXPHOS). AMPK is crucial for OXPHOS in LSCs, and phosphorylates mitochondrial fission factor (MFF) which is involved in mitochondrial dynamics and promote mitochondrial fission　by recruiting the GTPase dynamin-related protein 1 (Drp1). To clarify the function of MFF and DNM1L in AML cells, we knocked down MFF or DNM1L in AML cell lines using shRNA system. Transduction of shRNA against mitochondrial fission genes induced growth inhibition compared with control. Extracellular flux analysis showed that deletion of MFF or DRP1 results in reduced mitochondrial respiration. Subsequently, we treated AML cell lines with Mdivi-1, which inhibits mitochondrial fission. The Mdivi-1 treatment inhibited cell proliferation and OXPHOS in AML cell lines. Our results showed that mitochondrial dynamics plays an important role in AML and is a potential therapeutic target in AML.

Free Research Field

小児血液腫瘍

Academic Significance and Societal Importance of the Research Achievements

小児急性白血病の生存率は大幅に向上したものの、一部においては未だ化学療法、造血幹細胞移植あるいは分子標的療法へ抵抗性を示すものがあり、新たな治療戦略の開発が急務である。本研究は、治療抵抗性の白血病原因遺伝子に特異的なエネルギー代謝表現型を明らかにすることで小児急性白血病をエネルギー代謝の観点から分類し、エネルギー代謝特性に適した治療法を開発することを目的とする。代謝特性を標的とした治療法は従来の化学療法と異なる治療戦略であり、抗がん剤治療、分子標的療法と併用することで相乗効果の可能性も有し、白血病の治療成績向上に繋がる可能性がある。