STAT3 and NF-κB cooperatively control in vitro spontaneous apoptosis and poor chemo-responsiveness in patients with chronic lymphocytic leukemia
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Feng-Ting Liu1, Li Jia2, Ping Wang1, Huaqing Wang3, Timothy W. Farren4 and Samir G. Agrawal2
1 Department of Radiobiology, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Centre for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
2 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
3 Department of Medical Oncology, Tianjin Union Medicine Center, Tianjin, China
4 Pathology Group, Blizard Institute, Queen Mary University of London, London, UK
Feng-Ting Liu, email:
Keywords: spontaneous apoptosis, chronic lymphocytic leukemia, STAT3, NF-kB, prognosis
Received: January 04, 2016 Accepted: March 29, 2016 Published: April 09, 2016
Chronic lymphocytic leukemia (CLL) is an adult disease characterized by in vivo accumulation of mature CD5/CD19/CD23 triple positive B cells and is currently incurable. CLL cells undergo spontaneous apoptosis in response to in vitro cell culture condition but the underlying mechanism is unclear. We hypothesize that the sensitivity of CLL cells to spontaneous apoptosis may be associated with the constitutive activities of transcription factors STAT3 and/or NF-κB. We now show that the sensitivity of fresh CLL cells to spontaneous apoptosis is highly variable among different patients during 48 hours’ cell culture and inversely correlated with in vivo constitutively activated STAT3 and NF-κB (p < 0.001). Both activated STAT3 and NF-κB maintain the levels of anti-apoptotic protein Mcl-1/Bcl-xL and autocrine IL-6 production. CLL cells with higher susceptibility to in vitro spontaneous apoptosis show the greatest chemosensitivity (p < 0.001), which is reflected clinically as achieving a complete response (CR) (p < 0.001), longer lymphocyte doubling times (p < 0.01), time to first treatment (p < 0.01), and progression free survival (p < 0.05). Our data suggest that the sensitivity of CLL cells to in vitro spontaneous apoptosis is co-regulated by constitutively activated STAT3 and NF-κB and reflects the in vivo chemo-responsiveness and clinical outcomes.
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