Wilms’ tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells

Abstract

Wilms' tumor gene 1 (WT1) is a transcription factor involved in developmental processes. In adult hematopoiesis, only a small portion of early progenitor cells express WT1, whereas most leukemias show persistently high levels, suggesting an oncogenic role. We have previously characterized oncogenic BCR/ ABL1 tyrosine kinase signaling pathways for increased WT1 expression. In this study, we show that overexpression of BCR/ ABL1 in CD34 þ progenitor cells leads to reduced expression of interferon regulatory factor 8 (IRF8), in addition to increased WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether WT1 might repress IRF8 expression. When analyzed in four leukemia mRNA expression data sets, WT1 and IRF8 were anticorrelated. Upon overexpression in CD34 þ progenitors, as well as in U937 cells, WT1 strongly downregulated IRF8 expression. All four major WT1 splice variants induced repression, but not the zinc-finger-deleted WT1 mutant, indicating dependence on DNA binding. A reporter construct with the IRF8 promoter was repressed by WT1, dependent on a putative WT1-response element. Binding of WT1 to the IRF8 promoter was demonstrated by chromatin immunoprecipitation. Our results identify IRF8 as a direct target gene for WT1 and provide a possible mechanism for oncogenic effects of WT1 in leukemia.

Regulation of the Interferon regulatory factor-8 (IRF-8) Tumor Suppressor Gene by the Signal Transducer and Activator of Transcription 5 (STAT5) Transcription Factor in Chronic Myeloid Leukemia

“…This suppression is not a general consequence of BCR-ABL activity, as down-regulation of CRKL has no effect on IRF-8 expression. Vidovic et al (41) reported that the WT1 (Wilms tumor gene 1) tumor suppressor inhibits IRF-8 transcription in a BCR-ABL-dependent manner. An interaction between WT1 and STAT3 has been reported; it is possible that WT1 and STAT5 could similarly act to regulate IRF-8 expression (42).…”

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) −KTS and +KTS isoforms in leukemic cells

“…Both isoforms are known from previous reports to be capable of both activation and repression. 43,[46][47][48][49][50] Our finding could indicate that, even though the dominant influence of both isoforms on the target genes seems to be activating, in our cellular context WT1 +KTS co-localizes more often than WT1 -KTS with repressive complexes. Importantly, it should be pointed out that our investigation was restricted to WT1 +17AA isoforms.…”

Regulation of myelopoiesis by the transcription factor IRF8

“…Several factors that repress Irf8 have been also reported, including STAT5 [54], C/EBPβ [47], GATA1 [55], WT1 [56], and BCR-ABL (see below). Interestingly, a recent study reported that myeloid-derived suppressor cells (MDSCs) develop by attenuating IRF8 expression via STAT3 and STAT5 [57].…”