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

Publication date: Available online 12 January 2017
Source:Cell Stem Cell
Author(s): Mark P. Chao, Andrew J. Gentles, Susmita Chatterjee, Feng Lan, Andreas Reinisch, M. Ryan Corces, Seethu Xavy, Jinfeng Shen, Daniel Haag, Soham Chanda, Rahul Sinha, Rachel M. Morganti, Toshinobu Nishimura, Mohamed Ameen, Haodi Wu, Marius Wernig, Joseph C. Wu, Ravindra Majeti
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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Teaser

Chao et al. show that MLL-rearranged AML patient cells can be reprogrammed into induced pluripotent stem cells (iPSCs). These cells reacquire leukemic properties and associated methylation/gene expression patterns after hematopoietic differentiation and provide a means to study the differential properties of specific disease subclones.


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