Liu Haiyan, Zhai Yuanmei, Zhao Wenli, Wan Yun, Lu Wei, Yang Shaoxin, Yu Yehua, Wei Yanyu, Li Zhiqiang, Shi Jun
Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Hematology, Shanghai Jiao Tong University School of Medicine Affiliated Tongren Hospital, Shanghai, China.
Cell Physiol Biochem. 2018;45(6):2389-2400. doi: 10.1159/000488225. Epub 2018 Mar 13.
BACKGROUND/AIMS: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism.
A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15).
In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P<0.001). Moreover, patients with a reduced adipocyte content exhibited longer relapse-free survival (RFS) (P<0.001). We also confirmed that GDF15 was overexpressed in mononuclear cells (MNCs) after treatment with chemotherapy drugs and partially blocked mesenchymal stem cells (MSCs) adipogenesis. Intriguingly, this inhibitory effect on adipogenesis was rescued by treatment with a neutralizing anti-GDF15 antibody.
Chemotherapy indirectly inhibited adipogenesis by promoting GDF15 secretion from BM MNCs, subsequently strengthening the efficacy of consolidation chemotherapy in patients with AML during CR.
背景/目的：化疗仍然是预防急性髓系白血病（AML）复发的主要策略。作为骨髓（BM）中最丰富的基质成分，骨髓脂肪细胞先前已被证明可促进白血病发生。本研究旨在进一步验证骨髓脂肪细胞是否对增强化疗疗效具有协同作用，并评估其潜在机制。
对80例处于缓解期的AML患者和71例对照受试者的骨髓活检进行回顾性研究，以定量分析骨髓脂肪细胞体积。采用毒性试验评估化疗药物对骨髓细胞的影响。通过抗体中和实验研究化疗调节骨髓脂肪细胞含量降低的可能机制，重点关注生长分化因子15（GDF15）。
在我们的研究中，AML完全缓解（CR）组的骨髓脂肪细胞含量明显低于对照组（P<0.001）。此外，脂肪细胞含量降低的患者无复发生存期（RFS）更长（P<0.001）。我们还证实，化疗药物治疗后，GDF15在单核细胞（MNCs）中过表达，并部分阻断间充质干细胞（MSCs）的脂肪生成。有趣的是，用抗GDF15中和抗体治疗可挽救这种对脂肪生成的抑制作用。
化疗通过促进BM MNCs分泌GDF15间接抑制脂肪生成，随后增强AML患者CR期巩固化疗的疗效。
