{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:16:36Z","timestamp":1793085396000,"version":"4.5.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,10]]},"abstract":"<jats:p>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 \u03b2-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving \u03b2-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\/\u03b2-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3\u03b2, axin 1, \u03b2-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3\u03b2 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 GSK3\u03b2 have enhanced \u03b2-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3\u03b2 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 GSK3\u03b2 in GMP LSC, enabling unphosphorylated \u03b2-catenin to participate in LSC self-renewal. Missplicing of GSK3\u03b2 represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.<\/jats:p>","DOI":"10.1073\/pnas.0900189106","type":"journal-article","created":{"date-parts":[[2009,2,23]],"date-time":"2009-02-23T20:46:20Z","timestamp":1235421980000},"page":"3925-3929","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":227,"title":["Glycogen synthase kinase 3\u03b2 missplicing contributes to leukemia stem cell generation"],"prefix":"10.1073","volume":"106","author":[{"given":"Annelie E.","family":"Abrahamsson","sequence":"first","affiliation":[{"name":"Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifat","family":"Geron","sequence":"additional","affiliation":[{"name":"Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Gotlib","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim-Hien T.","family":"Dao","sequence":"additional","affiliation":[{"name":"Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene F.","family":"Barroga","sequence":"additional","affiliation":[{"name":"Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel G.","family":"Newton","sequence":"additional","affiliation":[{"name":"Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis J.","family":"Giles","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center, San Antonio, TX 78229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Durocher","sequence":"additional","affiliation":[{"name":"Transgenomic Inc., Gaithersburg, MD 20878; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remi S.","family":"Creusot","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mobin","family":"Karimi","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Jones","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"Zehnder","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armand","family":"Keating","sequence":"additional","affiliation":[{"name":"Princess Margaret Hospital, Toronto, ON, Canada M5G2C4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Negrin","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving L.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center at Stanford, and Stanford Cancer Center, Stanford University School of Medicine,Palo Alto, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona H. 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