title: Glycogen synthase kinase 3beta missplicing contributes to 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 (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.
authors.affiliation: Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Annelie E
authors.initials: AE
authors.lastname: Abrahamsson
authors.forename: Ifat
authors.initials: I
authors.lastname: Geron
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Kim-Hien T
authors.initials: KH
authors.lastname: Dao
authors.forename: Charlene F
authors.initials: CF
authors.lastname: Barroga
authors.forename: Isabel G
authors.initials: IG
authors.lastname: Newton
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Durocher
authors.forename: Remi S
authors.initials: RS
authors.lastname: Creusot
authors.forename: Mobin
authors.initials: M
authors.lastname: Karimi
authors.forename: Carol
authors.initials: C
authors.lastname: Jones
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001752:Blast Crisis / Q000201:enzymology / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D055014:Granulocyte-Macrophage Progenitor Cells / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D033581:Stem Cell Transplantation
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3