Chidamide and venetoclax synergistically regulate the Wnt/β-catenin pathway by MYCN/DKK3 in B-ALL

B-cell acute lymphocytic leukemia (B-ALL) is a malignant proliferative B-lymphocyte disease. Although the outcome of B-ALL has greatly improved with combined chemotherapy, immunotherapy, and hematopoietic stem cell transplantation, some patients still experience drug resistance, relapse and a low long-term survival rate, therefore, finding novel approaches to improve the outcome of adult B-ALL patients is critical. Our previous studies revealed that the selective histone deacetylase inhibitor (HDACi) chidamide can inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN and increasing the expression of DKK3 in B-ALL cells. Some studies have indicated that histone deacetylase inhibitors (HDACis) can dysregulate the B-cell lymphoma-2 (BCL2) protein family, we speculate that chidamide and BCL2 inhibitor venetoclax synergistically inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN expression and increasing DKK3 expression. In our study, the in vitro and in vivo experiments confirmed that chidamide and venetoclax synergistically inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of HDAC and BCL2, inhibiting the Wnt/β-catenin signaling pathway and B-ALL cell proliferation. These findings indicate that the HDACi chidamide and the BCL2 inhibitor venetoclax can be used in combination to treat B-ALL, providing a new method and strategy for treating B-ALL.