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Signaling and Regulation

The Critical Role of the Colony-Stimulating Factor-1 Receptor in the Differentiation of Myeloblastic Leukemia Cells

Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, Department of Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia

Requests for reprints: John A. Hamilton, Arthritis and Inflammation Research Centre, University of Melbourne, Department of Medicine, The Royal Melbourne Hospital, Clinical Sciences Building, Royal Parade, Parkville, Victoria 3050, Australia. Phone: 613-8344-5480; Fax: 613-9347-1863. E-mail: jahami{at}unimelb.edu.au

How diverse stimuli control hemopoietic lineage development is unknown. An early event during induction of macrophage differentiation in the myeloblastic leukemia M1 cell line by different stimuli, such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), is expression of the colony-stimulating factor-1 receptor (CSF-1R). We report that expression of active CSF-1R in M1 cells accelerated their subsequent terminal differentiation into macrophages in response to LIF and IL-6 when compared with cells lacking the CSF-1R or expressing the receptor with compromised kinase activity; however, there was no requirement for signaling through the CSF-1R, for example, via endogenous CSF-1, during the actual LIF-induced and IL-6–induced differentiation stage. Differences were noted in the signaling pathways downstream of the LIF receptor depending on the presence of the CSF-1R. Both LIF and IL-6 gave an additive response with CSF-1, consistent with LIF and IL-6 acting via a different signaling pathway (signal transducer and activator of transcription 3 dependent) than CSF-1 (extracellular signal-regulated kinase dependent). Based at least on this cell model, we propose that terminal macrophage differentiation involves a critical priming or deterministic phase in which signaling by the CSF-1R prepares a precursor population for subsequent rapid terminal macrophage differentiation by diverse stimuli. We also propose that expression and activation of the CSF-1R explain much prior literature on macrophage lineage commitment in M1 leukemic cells and may be important in controlling the progression of certain myeloid leukemias. (Mol Cancer Res 2008;6(3):458–67)