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

• Published in: Haematologica (Roma) 2003-04, Vol.88 (4), p.416-428
• Main Authors: Bruserud, O, Hovland, R, Wergeland, L, Huang, TS, Gjertsen, BT
• Format: Article
• Language: English
• Subjects: Adult; Aged; Blast Crisis - pathology; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute - pathology; Male; Membrane Proteins - physiology; Middle Aged; Mutation; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - physiology; Signal Transduction
• ISSN: 0390-6078; 1592-8721

Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. [e-mail] BACKGROUND AND OBJECTIVES: 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. DESIGN AND 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. INTERPRETATION AND CONCLUSIONS: Intracellular signaling initiated by Flt3 ligation modulates the functional phenotype for native human AML blasts both with and without genetic Flt3 abnormalities.