title: Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors.
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.
authors.affiliation: III Medizinische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Amanda
authors.initials: A
authors.lastname: Parmar
authors.forename: Stefanie
authors.initials: S
authors.lastname: Marz
authors.forename: Sally
authors.initials: S
authors.lastname: Rushton
authors.forename: Christina
authors.initials: C
authors.lastname: Holzwarth
authors.forename: Katarina
authors.initials: K
authors.lastname: Lind
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Götze
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017154:Stromal Cells / Q000473:pathology*; D020080:Tandem Repeat Sequences; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3