title: Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples.
abstract: Induced pluripotent stem cells (iPSCs) can be generated by the expression of defined transcription factors not only from normal tissue, but also from malignant cells. Cancer-derived iPSCs are expected to provide a novel experimental opportunity to establish the disease model. We generated iPSCs from imatinib-sensitive chronic myelogenous leukemia (CML) patient samples. Remarkably, the CML-iPSCs were resistant to imatinib although they consistently expressed BCR-ABL oncoprotein. In CML-iPSCs, the phosphorylation of ERK1/2, AKT, and JNK, which are essential for the maintenance of both BCR-ABL (+) leukemia cells and iPSCs, were unchanged after imatinib treatment, whereas the phosphorylation of signal transducer and activator of transcription (STAT)5 and CRKL was significantly decreased. These results suggest that the signaling for iPSCs maintenance compensates for the inhibition of BCR-ABL. CML-iPSC-derived hematopoietic cells recovered the sensitivity to imatinib although CD34(+)38(-)90(+)45(+) immature cells were resistant to imatinib, which recapitulated the pathophysiologic feature of the initial CML. CML-iPSCs provide us with a novel platform to investigate CML pathogenesis on the basis of patient-derived samples.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.forename: Masataka
authors.initials: M
authors.lastname: Hosoi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Taoka
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsu
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.forename: Koki
authors.initials: K
authors.lastname: Ueda
authors.forename: Kumi
authors.initials: K
authors.lastname: Nakazaki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016000:Cluster Analysis; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D046228:Microarray Analysis; D008962:Models, Theoretical; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D061251:Primary Cell Culture / Q000379:methods*
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one