Elucidating the contribution of the order of mutation acquisition to the clonal evolution of cancer using single-cell sequencing

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21546
• 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: Kyoto University
• Principal Investigator: Ogawa Seishi 京都大学, 医学研究科, 教授 (60292900)
• Co-Investigator(Kenkyū-buntansha): 昆 彩奈 京都大学, 医学研究科, 助教 (20772403)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: 単一細胞シーケンス / 遺伝子変異 / クローン進化 / 白血病

Outline of Final Research Achievements

Next-generation sequencing technology have revealed a comprehensive registry of driver mutations recurrently found in MDS patients. It has also been revealed that driver mutations are acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis. To understand the molecular mechanisms underlying the clonal evolution of leukemic clones, we generated several mice models-- 1) mice with different combination of driver mutations among the four driver mutations (SRSF2, STAG2, ASXL1, RUNX1) that is frequently observed in “chromatin-spliceosome” mutated AML subtypes, 2) pre-leukemic mice models using RCAS/TVA mediated gene transfer which harbored several combinations of mutations but the order of acquisition of the mutations are different. This study elucidated the contribution of the order of mutation acquisition to the clonal evolution of cancer.

Free Research Field

腫瘍学、血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

急性骨髄性白血病は、加齢に伴い造血幹細胞に遺伝子変異が蓄積して発症する腫瘍性疾患であり、高齢化に伴い患者数が増加している。造血幹細胞が複数の変異を獲得し、クローン選択によって高度な多様性をもった細胞集団が形成される分子メカニズムについては、発症の本質に関わる問題であるにもかかわらず、なお多くが不明である。本研究成果は、同一の遺伝子変異の組み合わせを有するものの、変異の獲得順序の違うマウスモデルを用いて、がんの発症におけるクローン選択の過程の分子病態を明らかにしたもので、将来的には、難治性がんの治療成績向上に資する可能性がある意義深い研究成果と考えている。