title: Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model.
abstract: The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wei
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Dongming
authors.initials: D
authors.lastname: Tan
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Guangsong
authors.initials: G
authors.lastname: Su
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota, United States of America.
authors.forename: Zhengwei J
authors.initials: ZJ
authors.lastname: Mao
authors.affiliation: Department of Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Singleton
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China; Thrombosis and Hemostasis Key Lab of the Ministry of Health, Soochow University, Suzhou, Jiangsu Province, PR China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu Province, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yin
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015996:Survival Rate; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C501332:ABT-737; D000964:Antimetabolites, Antineoplastic; D001713:Biphenyl Compounds; D051034:Inhibitor of Apoptosis Proteins; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D003561:Cytarabine