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Ferrata Storti Foundation
Haematologica 2020 Volume 105(11):2572-2583
Acute Myeloid Leukemia
Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis
Shaoxin Yang,1* Wei Lu,1* Chong Zhao,2 Yuanmei Zhai,3 Yanyu Wei,1 Jiali Liu,2 Yehua Yu,1 Zhiqiang Li4 and Jun Shi1
1Department of Hematology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine; 2Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital; 3Department of Hematology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine and 4Department of Blood Transfusion, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
*SY and WL contributed equally as co-first authors.
ABSTRACT
Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15), which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in patients with acute myeloid leukemia. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15- induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNA- sequencing screening and western blot analysis. Moreover, it was also con- firmed that FOXC1 combined with the TRPV4 promoter by chromatin immunoprecipitation with quantitative polymerase chain reaction experi- ments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an acute myeloid leukemia mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4a-phorbol 12,13-didecanoate partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for acute myeloid leukemia therapy.
Introduction
The development of acute myeloid leukemia (AML) is closely related to the bone marrow (BM) microenvironment.1,2 As a critical component of the BM microenvironment, BM adipocytes provide energy for both the infinite prolifera- tion of leukemia cells and the normal growth of hematopoietic stem cells.3,4 Leukemia cells proliferate to an overwhelming number in a limited marrow cavity, likely because these cells are more efficient in capturing energy for growth. Accordingly, BM adipocytes are remodeled in response to leukemia cells, generat- ing a pro-tumoral microenvironment.5,6 However, the mechanism whereby leukemia cell growth induces BM adipocyte remodeling is still unclear.
Induced BM adipocyte remodeling involves several specific processes, including lipolysis, dedifferentiation and lipid accumulation. Consequently, the remodeled adipocytes show morphological and functional changes.7 Breast cancer cells reportedly secrete soluble factor Wnt3a which reduces the number and size of adipocytes surrounding the malignant cells and thus contributes to disease devel-
Correspondence:
JUN SHI
junshi@sjtu.edu.cn
ZHIQIANG LI
kcb039@126.com
Received: April 30, 2019.
Accepted: December 18, 2019. Pre-published: December 19, 2019.
doi:10.3324/haematol.2019.225763 ©2020 Ferrata Storti Foundation
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