Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation

Annelie E. Abrahamsson, Ifat Geron, Jason Gotlib, Kim-Hien Dao, Charlene F. Barroga, Isabel G. Newton, Francis J. Giles, Jeffrey Durocher, Remi S. Creusot, Mobin Karimi, Carol Jones, James L. Zehnder, Armand Keating, Robert S. Negrin, Irving L. Weissman, Catriona H M Jamieson

Research output: Contribution to journalArticle

166 Citations (Scopus)

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 β-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving β-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/β-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3β, axin 1, β-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3β 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 GSK3β have enhanced β-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3β 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 GSK3β in GMP LSC, enabling unphosphorylated β-catenin to participate in LSC self-renewal. Missplicing of GSK3β represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.

Original languageEnglish (US)
Pages (from-to)3925-3929
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number10
DOIs
StatePublished - Mar 10 2009
Externally publishedYes

Fingerprint

Blast Crisis
Glycogen Synthase Kinase 3
Catenins
Leukemia
Stem Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Granulocyte-Macrophage Progenitor Cells
Neoplastic Stem Cells
Hematopoietic Stem Cells
Leukemia, Myeloid, Chronic Phase
TCF Transcription Factors
Wnt Signaling Pathway
Adenomatous Polyposis Coli
Cyclin D1
Regulator Genes
Lymphocyte Activation
Epigenomics
Phosphotransferases
Complementary DNA
Clone Cells

Keywords

  • Blast crisis chronic myeloid leukemia
  • Cancer stem cells
  • Self-renewal
  • Wnt pathway
  • Xenograft

ASJC Scopus subject areas

  • General

Cite this

Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. / Abrahamsson, Annelie E.; Geron, Ifat; Gotlib, Jason; Dao, Kim-Hien; Barroga, Charlene F.; Newton, Isabel G.; Giles, Francis J.; Durocher, Jeffrey; Creusot, Remi S.; Karimi, Mobin; Jones, Carol; Zehnder, James L.; Keating, Armand; Negrin, Robert S.; Weissman, Irving L.; Jamieson, Catriona H M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 10, 10.03.2009, p. 3925-3929.

Research output: Contribution to journalArticle

Abrahamsson, AE, Geron, I, Gotlib, J, Dao, K-H, Barroga, CF, Newton, IG, Giles, FJ, Durocher, J, Creusot, RS, Karimi, M, Jones, C, Zehnder, JL, Keating, A, Negrin, RS, Weissman, IL & Jamieson, CHM 2009, 'Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 10, pp. 3925-3929. https://doi.org/10.1073/pnas.0900189106
Abrahamsson, Annelie E. ; Geron, Ifat ; Gotlib, Jason ; Dao, Kim-Hien ; Barroga, Charlene F. ; Newton, Isabel G. ; Giles, Francis J. ; Durocher, Jeffrey ; Creusot, Remi S. ; Karimi, Mobin ; Jones, Carol ; Zehnder, James L. ; Keating, Armand ; Negrin, Robert S. ; Weissman, Irving L. ; Jamieson, Catriona H M. / Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 10. pp. 3925-3929.
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AU - Dao, Kim-Hien

AU - Barroga, Charlene F.

AU - Newton, Isabel G.

AU - Giles, Francis J.

AU - Durocher, Jeffrey

AU - Creusot, Remi S.

AU - Karimi, Mobin

AU - Jones, Carol

AU - Zehnder, James L.

AU - Keating, Armand

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