Aberrant lipid metabolism renders an aggressive behavior of T-lymphoblastic lymphoma in a MASH model

Liver involvement of lymphomas is not rare in clinical patients. Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) is well accepted as a potential precursor for liver cancer, but it is unknown whether MASH could promote extranodal infiltration of lymphoma. In this study, the subpopulation of tumor-initiating cells and Wnt signaling pathway activation were studied in T-lymphoblastic lymphoma cells. Tumor growth, Wnt/β-catenin signaling, and fenofibrate therapy were investigated in an MASH-lymphoma mouse model. We found that up-regulated Wnt/β-catenin and epithelial cell adhesion molecule signaling contributed to aggressive growth of T-lymphoblastic lymphoma in vitro and in vivo. Lack of fibroblast growth factor 21 (FGF21) worsened lipid metabolic disorder in the hepatic microenvironment which further promoted lymphoma growth in the MASH liver. Fenofibrate therapy upregulated the peroxisome proliferator-activated receptor alpha (PPAR-α)-FGF21 axis, thereby alleviated not only MASH but also liver infiltration of T-lymphoblastic lymphoma. In addition, down-regulated FGF21 but up-regulated Wnt signaling was found in T-cell lymphoma patient samples. In conclusion, aberrant lipid metabolism contributed to the aggressive growth of T-lymphoblastic lymphoma cells in MASH liver. Wnt/β-catenin signaling could be a potential lymphomagenetic mechanism for extranodal infiltration of T-lymphoblastic lymphoma. Fenofibrate has the potential to be an effective therapeutic strategy against liver infiltration of T-lymphoblastic lymphoma in MASH liver.