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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4695-4702.
Prepublished online as a Blood First Edition Paper on February 16, 2006; DOI 10.1182/blood-2005-10-4025.
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Submitted October 11, 2005
Accepted February 8, 2006
The anti-apoptotic gene A1/Bfl-1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy
Lesley A Simpson, Emily A Burwell, Kida A Thompson, Samira Shahnaz, Allen R Chen, and David M Loeb*
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
* Corresponding author; email: dmloeb{at}jhmi.edu.
Previous work has demonstrated that WT1 (-Ex5/-KTS) potentiates G-CSF-mediated granulocytic differentiation. This WT1 isoform suppresses Cyclin E, which may contribute to the pro-differentiation effect by slowing proliferation, but WT1 target genes that affect survival might also be involved. We screened a cDNA array and identified the bcl-2 family member A1/Bfl-1 as a new WT1 target gene in 32D cl3 murine myeloblast cells. Induction of WT1 (-Ex5/-KTS) expression is accompanied by upregulation of A1 on the cDNA array, and this upregulation was confirmed by semiquantitative RT-PCR. Moreover, both promoter-reporter assays and chromatin immunoprecipitation assays suggest that this isoform of WT1 activates the promoter directly. Constitutive expression of A1 in 32D cl3 cells induces spontaneous granulocytic differentiation, with both morphologic and cell surface antigen changes, as well as resistance both to chemotherapy and to withdrawal of IL-3. Finally, we note an association between WT1 expression and A1 expression in primary acute myeloid leukemia samples. Taken together, these results demonstrate that A1 is a new WT1 target gene involved in both granulocytic differentiation and resistance to cell death, and suggests that these genes might play an important role in the biology of high risk leukemias.
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