Linked Life Data

20130650

Source:http://linkedlifedata.com/resource/pubmed/id/20130650

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7281
pubmed:dateCreated
2010-2-4
pubmed:abstractText
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1476-4687
pubmed:author
pubmed:issnType
Electronic
pubmed:day
4
pubmed:volume
463
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
676-80
pubmed:meshHeading
pubmed-meshheading:20130650-Animals, pubmed-meshheading:20130650-Antineoplastic Agents, pubmed-meshheading:20130650-Apoptosis, pubmed-meshheading:20130650-Cell Differentiation, pubmed-meshheading:20130650-Cell Line, Tumor, pubmed-meshheading:20130650-Cell Nucleus, pubmed-meshheading:20130650-Disease Models, Animal, pubmed-meshheading:20130650-Enzyme Activation, pubmed-meshheading:20130650-Forkhead Transcription Factors, pubmed-meshheading:20130650-Humans, pubmed-meshheading:20130650-Leukemia, Myelogenous, Chronic, BCR-ABL Positive, pubmed-meshheading:20130650-Mice, pubmed-meshheading:20130650-Mice, Inbred C57BL, pubmed-meshheading:20130650-Neoplastic Stem Cells, pubmed-meshheading:20130650-Phosphorylation, pubmed-meshheading:20130650-Piperazines, pubmed-meshheading:20130650-Protein Kinase Inhibitors, pubmed-meshheading:20130650-Protein Transport, pubmed-meshheading:20130650-Protein-Tyrosine Kinases, pubmed-meshheading:20130650-Proto-Oncogene Proteins c-akt, pubmed-meshheading:20130650-Pyrimidines, pubmed-meshheading:20130650-Signal Transduction, pubmed-meshheading:20130650-Transforming Growth Factor beta, pubmed-meshheading:20130650-Tumor Stem Cell Assay
pubmed:year
2010
pubmed:articleTitle
TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia.
pubmed:affiliation
Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan. kazunaka@kenroku.kanazawa-u.ac.jp
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't