Molecular mechanisms of leukemic transformation of myelodysplastic syndromes.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09026
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: TOHYAMA Kaoru 川崎医科大学, 医学部, 教授 (80227561)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 骨髄異形成症候群 / 白血病化 / 遺伝子変異 / 網羅的ゲノム解析

Outline of Final Research Achievements

We established MDS92 cell line from a patient with myelodysplastic syndromes (MDS), and 5 sublines including MDS-L were isolated from MDS92. Further, MDS-L-2007 and MDS-LGF were obtained from MDS-L in the presence and absence of IL-3, respectively. Whole exome analyses demonstrated:TP53 mutation was found in the patient sample and was inherited by subsequent cell lines; CEBPA mutation was present in a part of the sample fraction; NRAS mutation emerged during culture. Such accumulated mutations could cause establishment of MDS92 cell line. Histone-H3(K27M) mutation (H3-K27M) was newly detected in MDS-L. MDS-L cells were a mixture of H3-K27M-mutant and wild-type clones, and this mutation was inherited by MDS-L-2007 but not MDS-LGF. H3-K27M-mutant clones exerted growth advantage in the presence of IL-3 but did not without IL-3 probably because of strict IL-3 dependency of the mutant clones. We propose this series of cell lines as an in vitro model for leukemic evolution of MDS.

Free Research Field

臨床検査医学

Academic Significance and Societal Importance of the Research Achievements

中高齢者に好発する血液難病であるMDSは急性白血病に移行すると著しく予後不良であり、この疾患の克服は社会的にも重要課題である。本研究は世界的にユニークなMDS細胞株およびそこから派生した急性白血病細胞株を用いて、MDSから急性白血病へ移行する分子機構の一端を解明したという学術的価値の高い内容である。また細胞株研究では新規薬剤の基礎的検討が繰り返し可能なことから、今後新たな治療法の開拓によってこの疾患の克服に繋げるという社会的にも期待できる成果といえる。