title: Growth differentiation factor 15 contributes to cancer-associated fibroblasts-mediated chemo-protection of AML cells.
abstract: Chemo-resistance is still a major obstacle in efforts to overcome acute myeloid leukemia (AML). An emerging concept has proposed that interactions between the bone marrow (BM) microenvironment and leukemia cells reduce the sensitivity of the leukemia cells to chemotherapy. As an important element of the tumor microenvironment, the cancer-associated fibroblasts (CAFs) are considered to be activated modulators in the chemo-resistance of many solid tumors. But their contribution to AML has yet to be fully understood. Here we report a critical role for CAFs which were thought to be a survival and chemo-protective factor for leukemia cells.
  
  
  
  A retrospective study on the BM biopsies from 63 primary AML patients and 59 normal controls was applied to quantitative analysis the fiber stroma in the BM sections. Then immunohistochemistry on the BM biopsies were used to detect the makers of the CAFs. Their effects on drug resistance of leukemia cells were further to be assessed by co-cultured experiments in vitro. Moreover, the possible mechanisms involved in CAF-mediated chemo-protection of AML cells was investigated by antibody neutralization and siRNA knockdown experiments, with particular emphasis on the role of GDF15.
  
  
  
  In our study, excessive reticular fibers in the BM led to higher frequency of relapse and mortality in primary AML patients, bringing the inspiration for us to investigate the functional roles of the fiber-devied cells. We declared that the CAF cells which expressed higher levels of FSP1, α-SMA or FAP protein were widely distributed in the marrow of AML. Then in vitro co-cultured tests showed that these CAFs could protect leukemia cell lines (THP-1/K562) from chemotherapy. Interestingly, this effect could be decreased by either treatment with a neutralizing anti-GDF15 antibody or knockdown GDF15 (with siGDF15) in CAFs. Furthermore, we also confirmed that the GDF15(+) cells mainly co-localized with FAP, which was identified as the typical phenotype of CAFs in the BM stroma.
  
  
  
  We firstly demonstrate that the functional CAFs are widespread within the BM of AML patients and should be a critical chemo-protective element for AML cells by producing amount of GDF15.
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Sihong
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Hematology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Weng
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South campus, Shanghai, 201400, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, 200011, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. junshi@sjtu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15
keywords: Acute myeloid leukemia; Bone marrow microenvironment; CAFs; GDF15