Abstract
Background:We have previously found that morphological remodeling of bone marrow adipocytes in acute myeloid leukemia (AML) patients is closely related to poor prognosis, and growth differentiation factor 15 (GDF15) may be a key factor in this pathological phenomenon.Aims:In this study, we further explored the mechanism of GDF15 regulating the bone marrow adipocyte remodeling from the perspective of calcium channel TRPV4.Methods:GDF15‐induced adipocytes were analyzed using gene expression profiling, and gene knockdown cells were generated by lentiviral‐mediated shRNA. Chip‐qPCR was used to evaluate the interaction between transcription factors and TRPV4. Signaling pathway downstream of GDF15 involved in adipocytes was analyzed by inhibitor experiments. An experimental AML mouse model was generated to investigate the role of TRPV4 in leukemia cell‐induced bone marrow adipocyte remodeling.Results:Western blot and RT‐qPCR showed that GDF15 could regulate TRPV4 expression in bone marrow adipocytes. In vitro, Transwell assay and neutralizing antibody assay further found that GDF15 secreted by leukemia cells regulated bone marrow adipocyte remodeling through TRPV4. The phenomenon was verified in obese C57/BL6 mice. Specific inhibition experiments showed that GDF15 secreted by leukemia cells combined with TGFβRII in bone marrow adipocytes, and then activated PI3K / AKT pathway. Using RNA‐Seq technique, we found that transcription factor FOXC1 mediated the inhibition of GDF15 on TRPV4 expression in bone marrow adipocytes, which causes the morphological remodeling of bone marrow adipocytes.Summary/Conclusion:GDF15 secreted by leukemia cells inhibits the expression of TRPV4 by regulating the transcription factor FOXC1 in bone marrow adipocytes, which promote the lipolysis of adipocytes. The free fatty acids released by this process provide energy support for the growth of leukemia cells. This paper provides a new perspective for the study of leukemia cell remodeling of bone marrow adipocyte microenvironment.
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