A β-catenin:MSI2 axis regulates the expression of LEF1 and subsequent human haematopoietic stem/progenitor cell proliferation

Wnt/β-catenin signaling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in many hematological malignancies. The central mediator, β-catenin, is an attractive therapeutic target in myeloid neoplasms however, the design of targeted agents has been hampered by a limited understanding of its molecular interactions in hematopoietic cells. To address this shortfall, we recently published the first β-catenin interactome (Morgan et al , 2019) in haematological cells and identified a plethora of novel partners which included the significant enrichment of RNA binding proteins (Wagstaff et al, 2022), including Musashi-2 (MSI2). MSI2 has been extensively implicated in normal HSC activity and also promotes aggressive myeloid leukemias where its expression confers inferior survival. Interaction between MSI2 and Wnt signalling has not previously been reported in a hematopoietic context. In this study we identify an interaction between MSI2 and β-catenin in both myeloid cell lines and primary AML patient samples where there is a significant degree of correlation between the proteins. We demonstrate that MSI2 can impact Wnt signalling output (TCF/LEF activity) through modulating LEF-1 expression and localization, and that MSI2 can further bind LEF1 transcript, an interaction augmented by β-catenin. Finally, we show that MSI2 mediated expansion of HSPCs could be partly driven through LEF1 regulation. To our knowledge this is the first study to demonstrate an interaction between MSI2 and β-catenin in haematopoietic cells, and shows the potential for β-catenin to cooperate with RBPs to govern HSPC proliferation. Finally, these data indicate β-catenin may also serve critical post-transcriptional functions (in addition to transcriptional roles) in haematopoietic cells, which could extend to regulating expression of Wnt signalling components.