Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2009-3-11
pubmed:abstractText
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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-10477735, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-10557058, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-12554650, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-12629218, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-12717451, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-12898635, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-14217141, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-14961028, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-15001769, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-15064419, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-15306667, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-15549107, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-16174694, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-16315267, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-16477019, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-16862118, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17051156, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17122772, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17151364, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17210912, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17283135, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17318191, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17395108, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17543867, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-17683539, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-18068630, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-2406902, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-267431, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-9212098, http://linkedlifedata.com/resource/pubmed/commentcorrection/19237556-9435248
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1091-6490
pubmed:author
pubmed:issnType
Electronic
pubmed:day
10
pubmed:volume
106
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3925-9
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation.
pubmed:affiliation
Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural