Elucidating the molecular mechanisms underlying the clonal evolution of leukemic stem cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16084
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Kon Ayana 京都大学, 医学研究科, 助教 (20772403)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨髄異形成症候群 / 急性骨髄性白血病 / クローン進化 / RCAS/TVAシステム / マウスモデル

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 founding clones, we generated two leukemic mice models, including MLL/AF9 driven leukemic mice models and pre-leukemic mice models using RCAS/TVA mediated gene transfer. By exome sequencing of serial BM samples of these mice models, we clarified the detailed clonal architecture over time. Further, we performed genome-wide screens using CRISPR/Cas9 technology to identify novel candidate genes that are essential for splicing factor mutated cells to be clonally selected. Findings from this study are expected to contribute significantly to the advance of understandings of MDS.

Free Research Field

血液腫瘍病態学

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群(MDS)および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、治療抵抗性のがんであるMDSの複雑な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。