Reprogramming technology revealed the genetic and functional diversity present in an individual myelodysplastic syndrome patient

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09847
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: Chonabayashi Kazuhisa 京都大学, iPS細胞研究所, 特定研究員 (00646010)
• Research Collaborator: Yoshida Yoshinori
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨髄異形成症候群 / 二次性急性骨髄性白血病 / リプログラミング / iPS細胞 / 腫瘍内多様性 / 新規治療薬

Outline of Final Research Achievements

We successfully generated multiple iPS cell lines from abnormal clones of patients with myelodysplastic syndromes or secondary AML (MDS/sAML) evolved from MDS. Hematopoietic progenitor cells (HPCs) differentiated from MDS-derived MDS-iPS cell lines showed decreased colony formation, whereas HPCs differentiated from sAML-derived MDS-iPS cell lines showed increased colony formation, compared with isogenic normal iPS cell lines, and induced lethal AML in transplanted immunodeficient mice. Next, we performed whole-exome analysis to find that some of the somatic mutations detected in bulk cells of MDS/sAML patients are shared in MDS-iPS cell lines but not in isogenic normal iPS cell lines. Furthermore, we performed coprehensive gene expression analysis in hematopoietic progenitor cells differentiated from MDS-iPS cell lines and isogenic normal iPS cell lines, identifying disease-specific expression change.

Free Research Field

血液腫瘍学、幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

予後不良のクローン性造血障害であるMDS/sAMLには病態を再現し解析するモデルが殆どなく、治療法の開発を可能にするツールが殆どないのが現状である。我々は患者から樹立した複数のMDS-iPS細胞株の網羅的ゲノム解析と、MDS-iPS細胞から再誘導された造血前駆細胞の分化能・造腫瘍能などの機能解析を組み合わせることにより、MDS/sAMLの腫瘍内多様性及び発症・進展機構を明らかした。