Expression of the Wilms' Tumor Suppressor Gene, WT1, Is Upregulated by Leukemia Inhibitory Factor and Induces Monocytic Differentiation in M1 Leukemic Cells

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Abstract
The Wilms' tumor gene, WT1, encodes a transcription factor of the Cys2-His2 zinc finger type. The functional significance of WT1 expression in leukemias, in addition to tissues and cell lines of hematopoietic origin, has not been determined. Using the murine myeloblastic leukemia cell line M1 as a model for macrophage differentiation, expression of WT1 is shown to be activated in M1 cells 24 hours after differentiation induction by leukemia inhibitory factor (LIF). Upregulation ofWT1 in these cells is associated with cellular differentiation, coinciding with expression of the monocyte/macrophage marker c-fms, and the appearance of mature cells. WT1 isoforms lacking the KTS insert are unable to be ectopically expressed in M1 cells. Stable expression of the WT1 isoforms containing the KTS insert leads to spontaneous differentiation of the M1 myeloblasts through the monocytic differentiation pathway. These cells express c-fms,in addition to the myeloid-specific cell surface marker Mac-1. Exposure of these cells to LIF results in the rapid onset of terminal macrophage differentiation, accompanied by apoptotic cell death. These results show that the WT1 gene is an important regulator of M1 cell monocytic differentiation in vitro, and suggests a potential role for this gene in the molecular control of hematopoiesis.