title: Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells.
abstract: A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia cells, we discovered olfactomedin 4 (OLFM4) as a novel factor that contributes to survival and growth of somatic lin(-)CD34(+) cells from bone marrow of patients with CML in chronic phase, but not primitive hematopoietic cells from normal bone marrow. Overall, this study shows the feasibility and advantages of using reprogramming technology to develop strategies for targeting primitive leukemia cells.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792, United States.
authors.forename: Kran
authors.initials: K
authors.lastname: Suknuntha
authors.affiliation: Department of Medicine, Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0820, United States.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, United States.
authors.forename: Lihong
authors.initials: L
authors.lastname: Tao
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, United States.
authors.forename: Kejin
authors.initials: K
authors.lastname: Hu
authors.affiliation: Morgridge Institute for Research, Madison, WI 53707, United States.
authors.forename: Brian E
authors.initials: BE
authors.lastname: McIntosh
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792, United States.
authors.forename: David
authors.initials: D
authors.lastname: Yang
authors.affiliation: Morgridge Institute for Research, Madison, WI 53707, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Swanson
authors.affiliation: Morgridge Institute for Research, Madison, WI 53707, United States.
authors.forename: Ron
authors.initials: R
authors.lastname: Stewart
authors.affiliation: Department of Medicine, Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0820, United States.
authors.forename: Jean Y J
authors.initials: JYJ
authors.lastname: Wang
authors.affiliation: Morgridge Institute for Research, Madison, WI 53707, United States; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53707, United States; Department of Molecular, Cellular & Developmental Biology, University of California, Santa Barbara, CA 93106, United States.
authors.forename: James
authors.initials: J
authors.lastname: Thomson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792, United States; Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, United States. Electronic address: islukvin@wisc.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Slukvin
mesh_terms: D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology*; D014407:Tumor Cells, Cultured