Affordable Access

deepdyve-link
Publisher Website

Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors.

Authors
  • Parmar, Amanda
  • Marz, Stefanie
  • Rushton, Sally
  • Holzwarth, Christina
  • Lind, Katarina
  • Kayser, Sabine
  • Döhner, Konstanze
  • Peschel, Christian
  • Oostendorp, Robert A J
  • Götze, Katharina S
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jul 01, 2011
Volume
71
Issue
13
Pages
4696–4706
Identifiers
DOI: 10.1158/0008-5472.CAN-10-4136
PMID: 21546568
Source
Medline
License
Unknown

Abstract

Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34(+) progenitors from patients with FLT3-ITD(+) or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD(+) and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD(+) and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD(+) but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD(+) AML. Further, we defined a specific interaction between FLT3-ITD(+) progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone.

Report this publication

Statistics

Seen <100 times