The antiapoptotic gene A1/BFL1 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, David M. Loeb

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Previous work has demonstrated that WT1 (-Ex5/-KTS) potentiates granulocyte colony-stimulating factor (G-CSF)-mediated granulocytic differentiation. This WT1 isoform suppresses cyclin E, which may contribute to the prodifferentiation effect by slowing proliferation, but WT1 target genes that affect survival might also be involved. We screened a cDNA array and identified the bCL2 family member A1/BFL1 as a new WT1 target gene in 32D cl3 murine myeloblast cells. Induction of WT1 (-Ex5/-KTS) expression is accompanied by up-regulation of A1 on the cDNA array, and this up-regulation was confirmed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Moreover, both promoterreporter 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 interleukin-interleukin-3 (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.

Original languageEnglish (US)
Pages (from-to)4695-4702
Number of pages8
JournalBlood
Volume107
Issue number12
DOIs
StatePublished - Jun 15 2006
Externally publishedYes

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Chemotherapy
Genes
Drug Therapy
Oligonucleotide Array Sequence Analysis
Assays
Protein Isoforms
Up-Regulation
Complementary DNA
Granulocyte Precursor Cells
Cyclin E
Chromatin Immunoprecipitation
Interleukin-3
Interleukins
Polymerase chain reaction
Granulocyte Colony-Stimulating Factor
Cell death
Transcription
Surface Antigens
Acute Myeloid Leukemia
Reverse Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. / Simpson, Lesley A.; Burwell, Emily A.; Thompson, Kida A.; Shahnaz, Samira; Chen, Allen R.; Loeb, David M.

In: Blood, Vol. 107, No. 12, 15.06.2006, p. 4695-4702.

Research output: Contribution to journalArticle

Simpson, Lesley A. ; Burwell, Emily A. ; Thompson, Kida A. ; Shahnaz, Samira ; Chen, Allen R. ; Loeb, David M. / The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. In: Blood. 2006 ; Vol. 107, No. 12. pp. 4695-4702.
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