Data from Fms-like Tyrosine Kinase 3 Ligand Stimulation Induces <i>MLL</i>-Rearranged Leukemia Cells into Quiescence Resistant to Antileukemic Agents

Abstract

<div>Abstract<p>Fms-like tyrosine kinase 3 (FLT3) is highly expressed in acute lymphoblastic leukemia with the <i>mixed-lineage leukemia</i> (<i>MLL</i>) gene rearrangement refractory to chemotherapy. We examined the biological effect of FLT3-ligand (FL) on 18 B-precursor leukemic cell lines with variable karyotypic abnormalities, and found that nine of nine <i>MLL</i>-rearranged cell lines with wild-type FLT3, in contrast to other leukemic cell lines, are significantly inhibited in their proliferation in a dose-dependent manner by FL. This inhibition was due to induction of the G<sub>0</sub>-G<sub>1</sub> arrest. A marked up-regulation of p27 by suppression of its protein degradation and an abrogation of constitutive signal transducers and activators of transcription 5 phosphorylation were revealed in arrested leukemia cells after FL stimulation. Importantly, FL treatment rendered not only cell lines but also primary leukemia cells with <i>MLL</i> rearrangement resistant to chemotherapeutic agents. <i>MLL</i>-rearranged leukemia cells adhering to the bone marrow stromal cell line, which expresses FL as the membrane-bound form, were induced to quiescent state resistant to chemotherapeutic agents, but their chemosensitivity was significantly restored in the presence of neutralizing anti-FL antibody. The FL/FLT3 interaction between leukemia cells and bone marrow stromal cells expressing FL at high levels should contribute, at least in part, to persistent minimal-residual disease of <i>MLL</i>-rearranged leukemia in bone marrow. [Cancer Res 2007;67(20):9852–61]</p></div>