Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease

被引：106

作者：

Chao, Mark P. ^{[1
,2
]}

Gentles, Andrew J. ^{[1
,3
]}

Chatterjee, Susmita ^{[1
]}

Lan, Feng ^{[1
]}

Reinisch, Andreas ^{[1
]}

Corces, M. Ryan ^{[1
]}

Xavy, Seethu ^{[1
]}

Shen, Jinfeng ^{[1
]}

Haag, Daniel ^{[1
]}

Chanda, Soham ^{[1
]}

Sinha, Rahul ^{[1
]}

Morganti, Rachel M. ^{[1
]}

Nishimura, Toshinobu ^{[1
]}

Ameen, Mohamed ^{[1
]}

Wu, Haodi ^{[1
]}

Wernig, Marius ^{[1
]}

Wu, Joseph C. ^{[1
,4
]}

Majeti, Ravindra ^{[1
,2
]}

机构：

[1] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

[3] Stanford Univ, Stanford Ctr Canc Syst Biol, Stanford, CA 94305 USA

[4] Stanford Univ, Stanford Cardiovasc lar Inst, Stanford, CA 94305 USA

来源：

CELL STEM CELL | 2017年 / 20卷 / 03期

关键词：

PLURIPOTENT STEM-CELLS; DNA METHYLATION; HEMATOPOIETIC DIFFERENTIATION; RAS PATHWAY; HOX GENES; MUTATIONS; CANCER; GENERATION; EXPRESSION; INDUCTION;

D O I：

10.1016/j.stem.2016.11.018

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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.

引用

页码：329 / +

页数：23

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