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pubmed-article:21689085pubmed:abstractTextThe efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.lld:pubmed
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pubmed-article:21689085pubmed:copyrightInfo© 2011 Blackwell Publishing Ltd.lld:pubmed
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pubmed-article:21689085pubmed:articleTitleTyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations.lld:pubmed
pubmed-article:21689085pubmed:affiliationSection of Haemato-Oncology, The Institute of Cancer Research, Sutton, Surrey Department of Clinical Cytogenetics, The Royal Marsden Hospital, Sutton, Surrey. Caroline.Alvares@icr.ac.uklld:pubmed
pubmed-article:21689085pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:21689085pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed