Development of Innovative Childhood Leukemia Therapy Using the Nucleolar Stress Response

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16929
• 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: Kagoshima University
• Principal Investigator: Nakagawa Shunsuke 鹿児島大学, 鹿児島大学病院, 医員 (60789973)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 小児急性リンパ性白血病 / 核小体ストレス応答 / 薬剤抵抗性 / P53

Outline of Final Research Achievements

The nucleolar stress response is a tumor suppressor mechanism that suppresses MDM2 via RPL11 and activates p53. Since TP53 mutations are rarely observed in pediatric B-cell precursor cell acute lymphoblastic leukemia (BCP-ALL), the nucleolar stress response is considered a good therapeutic target.
In this study, we first demonstrated that the nucleolar stress response is functional in pediatric BCP-ALL using cell lines. Next, among the drugs used in the treatment of pediatric BCP-ALL, we found that four drugs induced the nucleolar stress response. Analysis of clinical samples showed that RPL11 tended to be decreased at the time of relapse. The results suggest that dysfunction of the nucleolar stress response may be associated with recurrence.

Free Research Field

小児血液がん

Academic Significance and Societal Importance of the Research Achievements

本研究は小児BCP-ALLで核小体ストレス応答が機能することを明らかにし，これまでに核小体ストレス応答を誘導することが報告されていない４つの抗腫瘍薬の新たな作用機序を明らかにした点で学術的意義がある。また，臨床的検体を用いた検討では，核小体ストレス応答の機能低下が再発や薬剤抵抗性に関連する可能性を示した。以上のことから，核小体ストレス応答が小児BCP-ALLの再発や治療抵抗性を克服するための治療標的となり得ることを示し，小児BCP-ALLの新たな治療戦略を構築するための材料となる点において，社会的な意義があると考える。