Missplicing Of Glycogen Synthase Kinase 3 Beta: A Potential Mechanism Of Blast Crisis Chronic Myeloid Leukemia Stem Cell Generation

Abstract Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis, characterized by aberrant activation of β-catenin within granulocyte-macrophage progenitors (GMP). Here we show that blast crisis CML myeloid progenitors can serially transplant leukemia in immunocompromised mice, and thus are enriched for leukemia stem cells (LSC). Genomic DNA and cDNA sequencing analysis of Wnt/β-catenin pathway regulatory genes including APC, GSK3β, axin 1, β-catenin, LEF-1, cyclin D1 and c-myc in 49 normal and 51 CML HSC, GMP and lineage-positive populations revealed that in 57% of blast crisis samples a novel in-frame splice deletion of the GSK3β kinase domain occurred in blast crisis CML GMP, but not blasts found in blast crisis or normal progenitors. CML progenitors with misspliced GSK3β have enhanced β-catenin expression as well as serial engraftment potential. We propose that chronic phase CML is initiated by BCR-ABL expression in an HSC clone but that progression to blast crisis may include missplicing of GSK3β in GMP LSC, enabling unphosphorylated β-catenin to participate in LSC self-renewal. Missplicing of GSK3β represents an unique mechanism for the emergence of blast crisis CML LSC, is a potential diagnostic indicator of disease progression and represents a novel therapeutic target in blast crisis CML. As the first description of GSK3β dysregulation in cancer, this research provides a focal point for investigating whether GSK3β missplicing also triggers β-catenin activation in other CSC.