Abstract
Abstract 3598
Signal transducer and activator of transcription 3 (STAT3) proteins have been found to play an important role in cancer cell survival and proliferation. The activation of STAT3 signalling pathways require interleukin-6 (IL6) and tyrosine kinase (JAK2) phosphorylation. Previous studies have shown that in patients with CLL elevated levels of serum IL6 correlate with adverse disease features and shorter survival.
We investigated the relationship of CLL cell autocrine IL6 production, STAT3 activation and apoptosis resistance. Thirty-six CLL patients with high lymphocyte counts were investigated. Westen blot, flow cytometry, gene transfection and fluorescent microscopy techniques were used.
Autocrine IL6 production in CLL cells cultured for 24 hours was higher in Binet stage B/C patients (61pg/ml, range 1.4–297pg/ml) as compared with stage A patients (6.1pg/ml, range 0–23pg/ml) (p=0.02). Patients with high autocrine IL6 production had a higher ratio of phosphorylated STAT3/ total STAT3, indicating a high level of STAT3 activation and apoptosis resistance. Activation of the IL6/JAK2/STAT3 pathway by exogenous IL6 led to increased expression of anti-apoptotic proteins Mcl-1 and Bcl-xl. STAT3 activation by exogenous IL6 led to increased resistance of CLL cells to spontaneous in vitro apoptosis (mean increase in viable cells over control: 15%, range 2–36%; p=0.00008). This was associated with preservation of mitochondrial function: decreased cytochrome C release (p=0.004), mitochondrial membrane potential collapse (p=0.0004) and ROS generation (p=0.0007). This study demonstrates that higher autocrine IL6 production by CLL correlates with STAT3 activation and apoptosis resistance in CLL. The IL6/JAK2/STAT3 signal pathway may reveal new therapeutic targets.
Gribben:Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.
Author notes
Asterisk with author names denotes non-ASH members.
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