title: c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a malignant and aggressive disease not sensitive to chemotherapy. The dynamic interaction between AML cells and bone marrow (BM) microenvironment plays a critical role in response of this disease to chemotherapy. It is reported that mesenchymal stromal cells (MSC) are essential component of bone marrow microenvironment which affects the survival of AML cells. The aim of our research is to elucidate the mechanism of drug resistance of AML cells associated with MSC. We found that adhesion of AML cell lines U937, KG1a and primary AML cells to MSC inhibited cytotoxic drug-induced apoptosis. Western blot showed that c-Myc of AML cells cocultured with stroma was up-regulated. Treatment with 10058-F4, a small molecule inhibitor of MYC-MAX heterodimerization, or c-Myc siRNA significantly induced apoptosis. Western blot analysis further showed that inhibition of c-Myc induced expression of caspases-3, cleavage of PARP and reduced expression of Bcl-2, Bcl-xL and vascular endothelial growth factor (VEGF). Thus, we conclude that MSCs protected leukemia cells from apoptosis, at least in part, through c-Myc dependent mechanisms, and that c-Myc contributed to microenvironment-mediated drug resistance in AML. In summary, we declared that c-Myc is a potential therapeutic target for overcoming drug resistance in AML.
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Shanqi
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematology, First Affiliated Hospital of Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Fulian
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, First Affiliated Hospital of Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: Wanming
authors.initials: W
authors.lastname: Da
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: yizhuozhang111@163.com.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Acute myeloid leukemia; Apoptosis; Bone marrow stromal cells; Drug resistance; c-Myc