TI - Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation . AB - 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 ( CP ) in hematopoietic stem cells ( HSC ) that harbor the BCR-ABL translocation , to blast crisis ( BC ) , characterized by aberrant activation of beta-catenin within granulocyte-macrophage progenitors ( GMP ) . A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving beta-catenin activation . Here we show that BC CML myeloid progenitors , in particular GMP , serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells ( LSC ) . Notably , cDNA sequencing of Wnt/beta-catenin pathway regulatory genes , including adenomatous polyposis coli , GSK3beta , axin 1 , beta-catenin , lymphoid enhancer factor-1 , cyclin D1 , and c-myc , revealed a novel in-frame splice deletion of the GSK3beta kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors . Moreover , BC CML progenitors with misspliced GSK3beta have enhanced beta-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3beta reduces both in vitro replating and leukemic engraftment . We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3beta in GMP LSC , enabling unphosphorylated beta-catenin to participate in LSC self-renewal . Missplicing of GSK3beta represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target .