The essential transcriptional factor and its genomic element for the development of p53-deficient tumors

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22724
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: Nagasaki University
• Principal Investigator: ITO Kosei 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (00332726)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: T細胞リンパ腫 / p53 / c-Myc / Runx / 骨肉腫

Outline of Final Research Achievements

p53 deficiency and Myc dysregulation are the most frequently associated with human cancers. We have shown that Runx3 plays a role as a central oncogenic role mediating p53 inactivation and Myc upregulation via mR1; the essential genome element for Myc upregulation in osteosarcomagenesis. Here we focus on thymic lymphoma, which accounts for majority of tumours generated by systemic p53 deletion in mice. Mice lacking p53 specifically in T cells mostly succumbed to thymic lymphoma, certifying this Lck-Cre;p53F/F (LP) mouse line as a rational model to study the tumour. Depletion of Runx1, but not Runx3, effectively extended the lifespan of LP mice, phenocopying Myc-depleted LP mice. LP mice with specific mR1 disruption also presented a reduced thymic lymphoma incidence and thus an improved lifespan. These results suggest that Myc upregulation by Runx via mR1 is a common molecular basis for the pathogenesis of p53-deficient tumors across cancer types.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

極めて広範にヒトがんに関与する、p53の不活化とMycの活性化が、mR1とRunxの介在で機能的に連結した。細胞の腫瘍化は複雑であると考えられているが、実際には、根底にシンプルな共通基盤が存在し、そこに関与する責任因子や特定のゲノムエレメントをターゲットにすることで、それを制御できる可能性がある。
現在の抗がん政略は、テーラーメイド医療に代表させるように、個々の遺伝子異常に、個々に特化した分子標的薬で対処している。今回の成果は、この複雑な治療戦略を根本から見直すきっかけを与えている。