title: The novel structure make LDM effectively remove CD123+ AML stem cells in combination with interleukin 3.
abstract: CD123 became a therapeutic target for acute myelocytic leukemia(AML) because of its overexpression only on AML stem cells. It is α subunit of interleukin-3 (multi-CSF, IL3) receptor. Lidamycin(LDM) is a novel antibiotic composed of an apoprotein (LDP) and a chromophore (AE). We cloned, expressed and isolated IL3LDP fusion protein first then assembled with AE in vitro. We found that131/132 amino acids of IL3 were the key factors for IL3 fusion protein stability and I131L/F132L mutation effectively improved the IL3 fusion protein stability. The toxicity of IL3LDM to CD123+ tumor cells was 2-10 times compared to LDM alone and 10000 times compared to ADR. Meanwhile, IL3LDM impaired the colony-forming ability of CD123+ stem-like cells but not to CD123 negative normal cord blood cells. Three drug delivery methods in vivo were adopted: prophylactic treatment and single/multiple-dosing administration. The tumor-free survival extended to 120 d and cancer cell invasion significantly decreased after IL3LDM continuous multiple treated. Moreover, IL3LDM had been shown to modulate apoptosis by arrested cell cycle in G2/M phase. Therefore, IL3LDM is expected to be a new drug for leukemia target therapy.
authors.affiliation: a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b Department of biochemistry ; Microbiology and Immunology ; Faculty of Medicine ; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.affiliation: c Institute of Medicinal Biotechnology Academy of Medical Sciences & Peking Union Medical College ; Beijing , China.
authors.forename: Rizan
authors.initials: R
authors.lastname: Shi
authors.affiliation: a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: d Department of Pharmacology ; Shanxi Medical University ; Taiyuan, Shanxi , PR China.
authors.forename: Qingfang
authors.initials: Q
authors.lastname: Miao
authors.affiliation: e Affiliated People's Hospital of Jiangsu University ; Zhenjiang, Jiangsu , PR China.
authors.forename: Zhao-Qun
authors.initials: ZQ
authors.lastname: Deng
authors.affiliation: e Affiliated People's Hospital of Jiangsu University ; Zhenjiang, Jiangsu , PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: d Department of Pharmacology ; Shanxi Medical University ; Taiyuan, Shanxi , PR China.
authors.forename: Yongsu
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
authors.affiliation: a State Key Laboratory of Experimental Hematology ; Institute of Hematology & Hospital of Blood Diseases ; Chinese Academy of Medical Sciences & Peking Union Medical College ; Tianjin , China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics*; D053650:Interleukin-3 Receptor alpha Subunit / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells
chemical_list: C115022:IL3RA protein, human; D007377:Interleukin-3; D053650:Interleukin-3 Receptor alpha Subunit
keywords: CD123; LDM; interleukin 3; leukemia stem cells; target therapy