Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities.
OBJECTIVE
Intracellular signaling initiated via Flt3 seems important in both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Flt3 is activated by binding of its natural Flt3-ligand (Flt3-L), but Flt3 genes with internal tandem duplications (Flt3-ITD) or Asp(D)-835 point mutations encode molecules with constitutive activation. The aim of this study was to compare functional effects of exogenous Flt3-L on AML blast populations with and without genetic Flt3 abnormalities.


METHODS
Native AML blasts were derived from 64 consecutive patients with high blast counts in peripheral blood, and in vitro models were used to characterize the Flt3-L effects.


RESULTS
The Flt3 protein levels showed a similar wide variation between AML blast populations with and without genetic Flt3 abnormalities. Flt3-L was an autocrine growth factor only for 2 patients. Flt3-ITD+ AML cells had lower responsiveness to exogenous cytokines than cell populations without Flt3 abnormalities, but exogenous Flt3-L increased blast proliferation both for patients without Flt3 abnormalities and patients with Flt3-ITD as well as D835 mutations. This enhancement was observed even in the presence of other exogenous cytokines and included clonogenic AML progenitors. Flt3-L inhibited proliferation only for 1 patient, but had divergent effects on AML blast cytokine release. Flt3-L affected AML blast differentiation (inhibition of erythroid colonies, increased neutrophil granulation) only in a minority of patients, whereas it had an anti-apoptotic effect for a larger subset of patients.


CONCLUSIONS
Intracellular signaling initiated by Flt3 ligation modulates the functional phenotype for native human AML blasts both with and without genetic Flt3 abnormalities.
Bruserud
Øystein
Ø
Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. oystein.bruserud@haukeland.no
Hovland
Randi
R
Wergeland
Line
L
Huang
Tien-Sheng
TS
Gjertsen
Bjørn Tore
BT
D000328:Adult; D000368:Aged; D001752:Blast Crisis / Q000473:pathology; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C084881:flt3 ligand protein; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3