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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2002-09-2972.
Submitted September 30, 2002
Accepted June 23, 2003
STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to Bryostatin 1
Traci E Battle and David A Frank*
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
* Corresponding author; email: david_frank{at}dfci.harvard.edu.
Bryostatin 1 is known to exhibit in vitro and in vivo activity against chronic lymphocytic leukemia (CLL) cells by inducing their further maturation into plasma-like cells. Signal transducer and activator of transcription (STAT) proteins play a central role in B lymphocyte growth and function and are aberrantly phosphorylated on serine residues in CLL cells. To determine whether STAT transcription factors are important in Bryostatin 1-induced differentiation of CLL cells, primary CLL cells were examined for signaling events following exposure to Bryostatin 1 in vitro. Western analysis and electrophoretic mobility shift assays revealed that Bryostatin 1 induced tyrosine phosphorylation and DNA binding of STAT1 yet there was no effect on constitutive serine phosphorylation of STAT1. Bryostatin 1-induced STAT1 activation occurred in a manner that was dependent upon protein kinase C (PKC), mitogen activated protein kinase (MAPK), and Janus tyrosine kinase (JAK) activation. Evidence indicates that Bryostatin 1 induces STAT1 activation through an IFN autocrine loop. However, STAT1 activation by IFN stimulation alone was not sufficient to induce differentiation. This is due to the broader effect on gene expression caused by Bryostatin 1 compared to IFN, as demonstrated by microarray analysis. Both up-regulation of CD22 expression and IgM production, markers of CLL differentiation, were inhibited by a decoy oligonucleotide for STAT1, indicating that STAT1 is necessary for Bryostatin 1-induced differentiation of CLL cells. This study implicates STAT transcription factors as important mediators of Bryostatin 1-induced differentiation of CLL cells and could possibly lead to improved therapeutic approaches for the treatment of CLL.
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