Rapid upregulation of CTGF under stress conditions is required for HSC maintenance through cross-talk of canonical Wnt and AKT signaling

Recently, mutations of additional sex comb-like 1 (ASXL1) have been identified as an independent poor prognostic factor in MDS patients. We previously demonstrated that C-terminal–truncating ASXL1 mutations (ASXL1-MT) inhibited myeloid differentiation and induced MDS-like disease in mice by inhibiting polycomb repressive complex 2–mediated methylation of histone H3K27. Intriguingly, the patients with ASXL1 mutation have significantly higher incidences of concurrent SET binding protein 1 (SETBP1) mutation than those with wild-type ASXL1, which prompted us to investigate whether SETBP1 mutation plays a critical role in leukemic transformation of MDS. Most SETBP1 mutations, such as D868N, have been shown to occur in the PEST domain of ski homology region, resulting in the prevention from proteasomal degradation. In in vitro experiment, the expression of both SETBP1-D868N and ASXL1-MT enhanced myeloid colony output, reinforced ASXL1-MT-induced differentiation block and inhibited apoptosis. Of note, SETBP1-D868N collaborated with ASXL1-MT in inducing MDS/AML in mice BMT model compared to control mice (0.0001). Using GSEA, we demonstrated that SETBP1-MT enriched hematopoietic stem cells-related genes and deregulated p53 and Myc pathway. In addition, SETBP1-MT inhibited PP2a leading to the activation of the Akt pathway and exhibited characteristic histone modification pattern. In conclusion, our data provide evidence for the role of SETBP1-MT in leukemic transformation and suggest the deregulated pathways as a potential therapeutic target in MDS to prevent disease progression.