Crosstalk between clonal hematopoiesis and solid tumors

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22554
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Goyama Susumu 東京大学, 医科学研究所, 准教授 (80431849)
• Co-Investigator(Kenkyū-buntansha): 坂本 毅治 東京大学, 医科学研究所, 准教授 (70511418)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: クローン性造血 / 固形腫瘍 / ASXL1

Outline of Final Research Achievements

Recent sequencing analyses have revealed that clonal expansion of hematopoietic cells with acquired somatic mutations is common in aged healthy individuals. This phenomenon is called clonal hematopoiesis (CH). The most frequently mutated genes in CH include DNMT3A, TET2, and ASXL1. Interestingly, CH is particularly prevalent in solid tumor patients and its presence has an adverse impact on their overall survival. Using knockin mice that express CH-associated ASXL1-mutant (ASXL1-MT), we found that T cell-specific expression of ASXL1-MT accelerated the growth of melanoma, lung and colon cancer cells in syngraft mouse cancer models. ASXL1-MT-expressing hematopoietic cells also promoted the development of spontaneous breast cancer in the MMTV-PyMT model. Furthermore, we found that ASXL1-MT caused T cell population imbalance with a substantial reduction of naive T cells. Our results raise the possibility that CH has a causal role to promote the growth of solid tumors.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

全身を流れる血液細胞の異常は万病の基となり、様々な疾患発症や老化の原因となる。近年のゲノム解析により、特定の遺伝子変異を持つ異常な血液細胞がクローン性に増殖する「クローン性造血」が、健康な高齢者の血液中にしばしば認められることがわかってきた。そして本研究により、クローン性造血原因遺伝子ASXL1の変異を持つ血液細胞が、固形腫瘍の発症・進展を促進していることが明らかとなった。この成果は、今後の血液細胞を標的としたがん予防やがん治療の開発に大いに貢献すると考えられる。