The Wilms' tumor gene 1 (WT1) and leukemia -new insights and further complexity

The Wilms tumor gene 1 (WT1) encodes a zinc-finger containing transcription factor which is highly expressed in immature hematopoietic progenitor cells. A high expression of WT1 and the presence of somatic mutations in acute leukemia indicate a role for WT1 in the pathogenesis of leukemia. The ojective of this thesis was to investigate the role of WT1 during human hematopoiesis and leukemia. To gain further insights in how wild type WT1 and mutant WT1 affect proliferation and differentiation of human hematopoietic progenitor cells, CD34+ progenitor cells from cord blood were transduced with wild type WT1 or with a mutant of WT1, lacking the entire zinc-finger region, thus incapable of binding DNA. In these experiments, WT1 but not mutant WT1 inhibited erythroid colony formation as well as erythroid differentiation in suspension cultures. Suprisingly, both WT1 and mutant WT1 were able to inhibit myeloid colony formation and stimulated myeloid differentiation of cells grown i suspension culture. These results suggest that the effects of WT1 are mediated by distinct molecular mechanisms that are both DNA-binding dependent and independent. To further characterize the DNA-binding dependent functions of WT1, a gene expression analysis of WT1-transduced CD34+ progenitor cells was performed to identify genes transcriptionally regulated by wild type WT1. We found that WT1 upregulated the expression of N-myc downstream regulated gene 2 (NDRG2) and downregulated interferon regulatory factor 8 (IRF-8). Using a bacterial II hybrid assay, we also identified cofilin 1 as a novel protein partner of WT1. Our data also indicate that BCR/ABL1 induce expression of the WT1 gene via the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway in the leukemic cell line K562. Given our finding that WT1 downregulated the expression of IRF-8, we propose that WT1 is a link between BCR/ABL1 and IRF-8. This provide a mechanistic explanation for BCR/ABL1 induced repression of IRF-8 and a general mechanism by which high expression of WT1 can contribute to leukemogenesis.

Grantor dc:publisher

Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University

Year dc:date

2006

Author dc:creator

• Svensson, Emelie

• Hematology
• onkologi
• cancer
• Haematology
• extracellular fluids
• Hematologi
• extracellulära vätskor
• Cytologi
• cancerology
• oncology
• Cytology
• Medicin (människa och djur)
• Medicine (human and vertebrates)
• Cofilin 1
• NDRG2
• IRF-8
• BCR/ABL1
• hematopoiesis
• Wilms´ tumor gene 1
• leukemia

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

urn:isbn:91-85559-03-2

OAI identifier oai:identifier

oai:lup.lub.lu.se:e3a5415e-9826-42af-93e0-f286340294e0