title: Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells.
abstract: Acute myeloid leukemia (AML) often relapses following chemotherapy-induced remission and is generally chemo-resistant. Given the potential role for cancer stem cells in relapse, targeting of the leukemia-initiating cell (LIC) in AML may provide improved outcome following remission induction. However, due to overlap in their self-renewal program with normal hematopoietic stem cells (HSCs), therapeutic targeting of the LIC may have an adverse effect on long-term hematopoietic recovery. Here we used a mouse model of relapsed AML to explore whether the hypoxia-inducible factor (HIF)1α inhibitor echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that echinomycin cured 40% to 60% of mice transplanted with relapsed AML. Bone marrow cells from the cured mice displayed normal composition of HSCs and their progenitors and were as competent as those isolated from nonleukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, echinomycin appeared to completely eliminate LICs because no leukemia could be propagated in vivo following serial transplantation. Taken together, our data demonstrate that in a mouse model of relapsed AML, low-dose echinomycin selectively targets LICs and spares normal hematopoiesis.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Fei
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Biology, North Carolina A&T State University, Greensboro, NC;
authors.forename: Kelsie M
authors.initials: KM
authors.lastname: Bernot
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Reuven
authors.initials: R
authors.lastname: Schore
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH; and.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC; Division of Pathology and Sheik Zayed Institute for Surgical Innovation, Children's Research Institute, Children's National Medical Center, Washington, DC.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D004448:Echinomycin / Q000494:pharmacology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004448:Echinomycin