Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis

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 acute myeloid leukemia (AML) patients. 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 (TGFβRII) 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-seq screening and Western blot analyse. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by the Chip-qPCR experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an AML mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4α-phorbol 12,13-didecanoate (4αPDD) 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 AML therapy.

Role of TRPV4 Channel in Human White Adipocytes Metabolic Activity

“…Previously, it was demonstrated that TRPV4 inhibition in bone marrow adipocytes increases ATGL and HSL expression levels and produces subsequent lipolysis increase during basal and IPT-stimulated conditions [ 31 ], similar to our results. In white adipocytes, TRPV4 channel activation reduced the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) [ 20 ], a key transcription factor that regulates lipolysis via ATGL and HSL expression [ 9 ].…”

Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

“…It has been reported that AML cells differentiate the residual BMAs into small adipocytes by secreting growth differentiation factor 15 (GDF15). Moreover, transient receptor potential vanilloid 4 mediates GDF15-induced remodeling of BM adipocytes (Yang et al, 2019). A recent study revealed that in patients with AML during complete remission, chemotherapy drugs indirectly blocked MSC adipogenesis, enhanced the efficacy of consolidated chemotherapy, and prevented relapse by promoting GDF15 secretion from BM mononuclear cells (Liu et al, 2018).…”

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

“…Later in a study exploring the mechanisms behind the remodeling of bone marrow adipocyte, Lu et al [ 67 ] reported that growth differentiation factor-15 (GDF15), a secreted propeptide highly expressed in leukemic cells, could promote the morphological transition of small adipocytes from larger adipocytes when released to the bone marrow cavity. they proceeded to elucidate that the down-regulation of TRPV4 (a calcium channel on the adipocyte membrane) mediated by GDF15 played an important role in the morphological transition process [ 68 ]. Previous study found that highly expressed lipolytic gene was expressed in small adipocytes in mice [ 69 ].…”