Tyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations.

C.L. Alvares, T. Schenk, S. Hulkki, T. Min, G. Vijayaraghavan, J. Yeung, D. Gonzalez, C.W. So, M. Greaves, I. Titley, K. Bartolovic, G. Morgan

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The 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.
Original languageEnglish
Pages (from-to)457-465
Number of pages9
JournalBritish Journal of Haematology
Volume154
Issue number4
DOIs
Publication statusPublished - Aug 2011

Keywords

  • Adult
  • Animals
  • Antigens, CD34
  • Antineoplastic Agents
  • Benzimidazoles
  • Cell Cycle
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Humans
  • Leukemia, Myeloid, Acute
  • Mice
  • Middle Aged
  • Mutation
  • Pilot Projects
  • Protein-Tyrosine Kinases
  • Quinolones
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Young Adult
  • fms-Like Tyrosine Kinase 3

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