Prevention of childhood acute leukemia by targeting pre-leukemic stem cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08754
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Ehime University
• Principal Investigator: Eguchi-Ishimae Minenori 愛媛大学, 医学部附属病院, 准教授 (50420782)
• Co-Investigator(Kenkyū-buntansha): 江口 真理子 愛媛大学, 医学系研究科, 教授 (40420781)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 小児白血病 / 前白血病幹細胞 / 白血病幹細胞 / 融合遺伝子

Outline of Final Research Achievements

Prevention of leukemic development is most effective treatment of pediatric leukemia. To clarify the process of leukemic stem cell (LSC) generation from pre-leukemic stem cells (pre-LSC), experimental model of pre-LSC was established using mouse embryonic stem (ES) cells expressing leukemia-specific fusion genes and patient-derived iPS cells. Hematopoietic progenitor cells derived from fusion gene-expressing mouse ES cells were not able to initiate leukemia by transplantation into immune-deficient mice, indicating that these cells were in pre-LSC state. After introducing insertional mutagenesis mouse ES cell-derived hematopoietic progenitor cells generate leukemia in transplanted mice. Hematopoietic progenitor cells obtained from patient-derived iPS cells harbored MLL fusion gene in low frequency, which was not detected in iPS from healthy controls. It was suggested that some, yet unknown genetic background of the patient may be involved in the generation of the MLL fusion gene.

Free Research Field

小児科学、血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

治療法の進歩により小児白血病の治療成績は近年大きく改善している。しかしながら強力な化学療法による副作用が成長障害などの長期的な後遺障害を引き起こすことも多い。白血病の発症予防が可能となれば小児白血病の予後の改善が期待できる。前白血病幹細胞は白血病幹細胞へ進展し、白血病発症の元となる重要な細胞である。白血病の発症予防のためには前白血病幹細胞の根絶が必須であり、その生存・維持のメカニズムと白血病幹細胞への進展のメカニズムが明らかになれば、新たな治療法の開発へつながり、小児白血病患者の予後改善が可能となる。