Abstract
The Wilms’ tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
Highlights
The Wilms’ tumour gene 1 transcription factor (WT1) was first identified as a tumour suppressor gene in Wilms' tumour [1, 2]
Wilms’ tumor gene 1 (WT1) is normally expressed in a small subset of CD34+ progenitor cells [7,8,9] and murine hematopoietic stem cells lacking WT1 are incapable of competing with normal stem cells in reconstitution [10]
Similar results with raised NAB2 mRNA levels (Figure 1B) and NAB2 protein (Figure 1C, D) were obtained upon transduction of the leukemic U937 cell line with WT1. These www.impactjournals.com/oncotarget results suggest that WT1 binds to and transactivates the NAB2 gene
Summary
The Wilms’ tumour gene 1 transcription factor (WT1) was first identified as a tumour suppressor gene in Wilms' tumour [1, 2]. Only a fraction of Wilms' tumours have WT1 inactivating mutations, and in other cases WT1 rather shows overexpression [3]. The Denys-Drash syndrome, caused by germ line mutations of WT1, shows the importance of WT1 for human renal and genital development [6]. In most acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) blast cells, WT1 is highly expressed and correlated to poor clinical outcome [13,14,15,16]. Upon forced overexpression, the WT1 protein interferes with differentiation of myeloid cell lines [18,19,20] and cooperates with the fusion protein RUNX1/ RUNX1T1 (AML1/ETO) in a rapid induction of leukemia www.impactjournals.com/oncotarget in transgenic mice, clearly demonstrating a leukemogenic role for WT1 [21]. Molecular mechanisms by which WT1 protein exerts its function are, incompletely understood
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