title: Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease.
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.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Department of Medicine, Division of Hematology, Stanford Medicine, CA 94305, USA. Electronic address: mpchao@stanford.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Stanford Center for Cancer Systems Biology, Stanford Medicine, CA 94305, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reinisch
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Corces
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Seethu
authors.initials: S
authors.lastname: Xavy
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haag
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Soham
authors.initials: S
authors.lastname: Chanda
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Morganti
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ameen
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University, CA 94305, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, CA 94305, USA; Department of Medicine, Division of Hematology, Stanford Medicine, CA 94305, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D001752:Blast Crisis / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D048430:Cell Shape; D065150:Cellular Reprogramming; D002869:Chromosome Aberrations; D002999:Clone Cells; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D010641:Phenotype
keywords: MLL; acute myeloid leukemia; epigenetics; induced pluripotent stem cells; reprogramming