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S. Yang et al.
motes lipolysis in BM adipocytes, contributing to their remodeling into small adipocytes in the pathogenesis of AML.
Moreover, we also found that treatment with the TRPV4 agonist 4aPDD rescued BM adipocyte remodel- ing, which was correlated with increased survival in AML-bearing mice, supporting a crucial role of TRPV4 in the growth and progression of AML. Although there are unstained positive white circles in the BM of AML mice (Figure 5A), we suspect that these circles may represent an increase in blood vessels or sinuses in the BM of these animals. Leukemia cells can promote angiogenesis, which in turn contributes to the proliferation of leukemia cells.48 Of course, it cannot be excluded that a few adipocytes were not stained positively. Many studies have also reported the effect of circulating factors in obese animals on leukemia.49,50 However, in our study, both experimen- tal groups and control groups were obese mice, and their basic background was the same. This should, therefore, have allowed us to control for the impact of the circulat-
ing factors, which sould not have been responsible for observed differences in mouse survival and other vari- ables. Future studies in vivo are needed to validate the spe- cific modulatory role of GDF15 on TRPV4.
In conclusion, leukemia cells activate a transcriptional network that includes GDF15-related-PI3K/AKT activa- tion and subsequent TRPV4 downregulation, which pro- motes BM adipocyte remodeling. The morphological adaptation of BM adipocytes and the modulation of lipo- lysis may represent a novel strategy for the treatment of hematologic malignancies, especially in elderly patients, whose aging and increased adiposity of the BM microen- vironment reduce the efficacy of cytotoxic chemotherapy.
Acknowledgments
The work was supported by grants from the National Natural Science Foundation of China (grant n. 81870132), Science and Technology Commission of Shanghai Municipality (grant n.18DZ2293500) and Shanghai Sailing Program (grant n. 18YF1419100).
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