Why target the WT1 gene?

Comment on Simpson et al, page 4695

In this issue of Blood, Simpson and colleagues describe the presence of the antiapoptotic gene A1/Bfl1 as a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy.

The WT1 gene is a zinc finger transcription factor that was originally identified as a tumor suppressor gene in children. It is one of at least 3 genes involved in the pathogenesis of Wilms tumor.¹ WT1 is expressed in many tissues, including hematopoietic stem cells.²  There are multiple hypotheses about this gene's role in leukemia. There is evidence that the WT1 gene has a role in the development and antiapoptotic mechanisms of myeloid lineage.³  Unfortunately, WT1 is expressed in lymphoid lineage cells as well as in other malignancies. Others suspect that WT1 is a surrogate marker of proliferation, due to its high levels of expression in most myeloid and lymphoid leukemias. Our group has also found high levels of expression in proliferating normal myeloid cells in culture.⁴  There are reports that some isoforms of WT1 either inhibit or potentiate myelopoiesis in cell cultures.³  Many series have been published using the overexpression of the WT1 gene as a marker of minimal residual disease (MRD), where the presence of expression of the WT1 gene correlates with a poor prognosis, primarily in patients with acute myeloid leukemia (AML).⁵  Nishida et al reported that the presence of the chimeric gene AML1-ETO also inhibits differentiation of myeloid progenitors by suppression of clonogenic progenitors but cannot induce AML by itself, requiring a second event. In mice, the use of a transduced WT1 transgene into transplanted BM cells with AML1-ETO induces AML.⁶  The speculation that this is primarily related to drug resistance, because chemotherapy agents induce apoptosis in susceptible cells, may be true; however, we will have to ask why that is the case, since this particular gene is also expressed in many other malignancies, including lymphoid malignancies, which are quite sensitive to chemotherapeutic agents.

The authors of this paper have very elegantly demonstrated in a murine cell line that the WT1 gene suppresses the expression of cyclin E, and they have identified that the A1 gene (BFL1 in humans) in the family of bcl-2 is implicated in differentiation and in resistance to apoptosis in hematopoietic cells. If WT1 does indeed regulate different bcl-2 family members, causing different effects depending on the cell line being investigated, the function of A1 might be related to differentiation as well as to apoptosis. The multiple reports that correlate high levels of expression of WT1 in AML with poor prognoses may suggest that there is a relationship between drug resistance and the regulation of WT1 to the bcl-2 family members such as A1. ▪