Generation and characterization of BCOR-ITD tumor models

• Project/Area Number: 18K07057
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Ueno Hitomi 国立研究開発法人国立成育医療研究センター, 小児血液・腫瘍研究部, 研究員 (30435630)
• Co-Investigator(Kenkyū-buntansha): 高田 修治 国立研究開発法人国立成育医療研究センター, システム発生・再生医学研究部, 部長 (20382856)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 小児腫瘍 / BCOR / ゲノム編集 / Bcor / ポリコーム / 腫瘍モデル / エピゲノム

Outline of Final Research Achievements

To elucidate how BCOR internal tandem duplication (BCOR-ITD) causes　tumorigenesis, we attempted to generate model mice and model cells with Bcor-ITD. In this study, we applied genome editing in fertilized eggs, which resulted in unintended mutations in some cells, making it difficult to create a line of Bcor-ITD mice. However, we succeeded in establishing Bcor-ITD positive ES cells and fibroblasts from heterozygote mice.
The Bcor-ITD-expressing fibroblast cell line showed an upward trend in the expression of Bcor compared to the wild-type expressing line. In fibroblasts, when the activated X chromosome was Bcor-ITD, the gene expression of Bcor tended to increase than that of the wild type.　This result is consistent with the over expression of BCOR-ITD in clear cell sarcoma of the kidney, suggests that mutation acquisition may result in regulated BCOR gene expression.

Academic Significance and Societal Importance of the Research Achievements

変異モデルは、様々な遺伝子変異の機能解析や治療薬開発に必須である。
本研究では小児固形腫瘍で発見したBCOR変異（BCOR-ITD）を有するマウスモデル細胞を作出し、その分子生物学的解析から腫瘍で認める特徴の一部が、変異獲得により生じていると推測できる結果を得た。また変異を有するES細胞を樹立したことにより、今後、BCOR-ITDによる異常な細胞分化や腫瘍化の観察について可能性が広がった。本研究の成果は、BCOR-ITD陽性腫瘍の解明に向けた足掛かりになったと考える。