β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells

SummaryIdentification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs.

► Differential activation of Wnt/β-catenin pathway is required for MLL LSC development
► Suppression of β-catenin reverses MLL LSCs to a pre-LSC like stage
► Down modulation of β-catenin impedes human AML proliferation
► Suppression of β-catenin sensitizes MLL LSCs to GSK3 inhibitors