title: A cell engineering strategy to enhance the safety of stem cell therapies.
abstract: The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer's increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Oricchio
authors.affiliation: Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eirini P
authors.initials: EP
authors.lastname: Papapetrou
authors.affiliation: Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lafaille
authors.affiliation: Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yosif M
authors.initials: YM
authors.lastname: Ganat
authors.affiliation: Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kriks
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega-Molina
authors.affiliation: Mouse Genetics Core, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Willie H
authors.initials: WH
authors.lastname: Mark
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Reuter
authors.affiliation: Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.affiliation: Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: wendelh@mskcc.org.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D060846:Cell Engineering; D002460:Cell Line; D064987:Cell- and Tissue-Based Therapy / Q000592:standards*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000000981:diagnostic imaging; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000628:therapy; D055495:Neurogenesis; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism; D011859:Radiography; D013963:Thyroid Hormones / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins