Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis

Abstract

The Dlx5 homeobox gene was first implicated as an oncogene in a T-ALL mouse model expressing myristoylated (Myr) Akt2. Furthermore, overexpression of Dlx5 was sufficient to drive T-ALL in mice by directly activating Akt and Notch signaling. These findings implied that Akt2 cooperates with Dlx5 in T-cell lymphomagenesis. To test this hypothesis, Lck-Dlx5;Lck-MyrAkt2 transgenic mice were generated. MyrAkt2 synergized with Dlx5 to greatly accelerate and enhance the dissemination of T-lymphomagenesis. RNA-seq analysis performed on lymphomas from Lck-Dlx5;Lck-MyrAkt mice revealed upregulation of genes involved in the Wnt and cholesterol biosynthesis pathways. Combined RNA-seq and ChIP-seq analysis of lymphomas from Lck-Dlx5;Lck-MyrAkt mice demonstrated that β-catenin directly regulates genes involved in sterol regulatory element binding transcription factor 2 (Srebf2)-cholesterol synthesis. These lymphoma cells had high Lef1 levels and were highly sensitive to β-catenin and Srebf2-cholesterol synthesis inhibitors. Similarly, human T-ALL cell lines with activated NOTCH and AKT and elevated LEF1 levels were sensitive to inhibition of β-catenin and cholesterol pathways. Furthermore, LEF1 expression positively correlated with expression of genes involved in the cholesterol synthesis pathway in primary human T-ALL specimens. Together, these data suggest that targeting β-catenin and/or cholesterol biosynthesis, together with AKT, could have therapeutic efficacy in a subset of T-ALL patients.

A survival prediction model and nomogram based on immune-related gene expression in chronic lymphocytic leukemia cells

“…These data represent different meanings of CDKN2A at different stages. SREBF2 expression is associated with a poor prognosis in T-cell lymphoma, AML, plasma cell myeloma and liver cancer (35)(36)(37)(38). There are no data on the impact of SREBF2 expression in CLL.…”

The Role of NKL Homeobox Genes in T-Cell Malignancies

“…DLX5 expression was also detected in primary human T-cell lymphoma samples while DLX6 tested negative [72]. Functionally, DLX5 promotes NOTCH-signalling and the AKT-pathway in a mouse model which may represent its main oncogenic function [73,74].…”

Orchestral role of lipid metabolic reprogramming in T-cell malignancy

“…Interestingly, the accumulation of intermediary metabolite of the cholesterol synthesis pathway, i.e., squalene, was reported in Jurkat cells ( 109 ). Moreover, oncogenic stimulus mediated by wnt signaling triggers the generation of T-cell lymphoma through the upregulation of cholesterol synthesis ( 110 ). The syntheses of fatty acid and lipid molecules in cells of T-cell cancer not only offer superior survival and proliferative ability but also play a critical role in oncogenic transformation ( Figure 3 ).…”