Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Chao, MP; Gentles, AJ; Chatterjee, S; Lan, F; Reinisch, A; Corces, MR; Xavy, S; Shen, J; Haag, D; Chanda, S; Sinha, R; Morganti, RM; Nishimura, T; Ameen, M; Wu, H; Wernig, M; Wu, JC; Majeti, R.
Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease.
Cell Stem Cell. 2017; 20(3): 329-344.
Doi: 10.1016/j.stem.2016.11.018
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- Co-Autor*innen der Med Uni Graz
- Reinisch Andreas
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- Abstract:
- 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. Copyright © 2016 Elsevier Inc. All rights reserved.
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