期刊
CELL STEM CELL
卷 20, 期 3, 页码 329-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2016.11.018
关键词
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资金
- A.P. Giannini Foundation
- Helen Hay Whitney Foundation
- Stanford Translational Research and Applied Medicine
- New York Stem Cell Foundation
- NIH [R01CA188055, R24 HL11756]
- Ludwig Cancer Institute
Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature. Epigenetic reprogramming was therefore not sufficient to eliminate leukemic behavior. This approach also allowed us to study the properties of distinct AML subclones, including differential drug susceptibilities of KRAS mutant and wild-type cells, and predict relapse based on increased cytarabine resistance of a KRAS wild-type subclone. Overall, our findings illustrate the value of AML-iPSCs for investigating the mechanistic basis and clonal properties of human AML.
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