title: STAT3 and NF-κB cooperatively control in vitro spontaneous apoptosis and poor chemo-responsiveness in patients with chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Feng-Ting
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Tianjin Union Medicine Center, Tianjin, China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pathology Group, Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Farren
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Samir G
authors.initials: SG
authors.lastname: Agrawal
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; C498143:RELA protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; D051020:bcl-X Protein
keywords: NF-kB; STAT3; chronic lymphocytic leukemia; prognosis; spontaneous apoptosis