title: CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia.
abstract: IL6 promotes tumor growth and signal transduction via both its membrane-bound (CD126) and soluble receptors (sCD126). We aimed to study whether the levels of CD126 expression in chronic lymphocytic leukemic (CLL) cells can predict in vitro and in vivo treatment response.
  
  
  
  The levels of membrane-bound CD126 expression were determined on freshly isolated CLL B cells (n = 58) using flow cytometry. These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6-mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated.
  
  
  
  CD126 surface expression was found in all cases and positively correlated with the levels of in vivo constitutive STAT3 activity. The levels of CD126 expression were significantly and positively correlated with the resistance of CLL cells to in vitro treatment with chlorambucil or fludarabine and poor in vivo treatment response of CLL patients. Blocking IL6 signaling with the anti-CD126 antibody, tocilizumab, had profound effects on STAT3-mediated survival and growth signals: decreased Mcl-1 and Bcl-xL, favoring an apoptotic profile; and decreased p27 with increased cyclin E and CDK2 expression, leading to cell-cycle shift from G0-G1 These tocilizumab-mediated changes induced chemosensitization in resistant CLL cells, with the greatest effect seen in cells with higher CD126 expression (P < 0.001).
  
  
  
  CLL cells with higher CD126 expression are more resistant to treatment in vivo and in vitro via IL6-CD126-STAT3 axis. Blocking CD126 using tocilizumab sensitizes CLL cells to chemotherapy. Clin Cancer Res; 22(10); 2462-9. ©2015 AACR.
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. liufengting@tjmuch.com s.g.agrawal@qmul.ac.uk.
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, United Kingdom.
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: Division of Haemato-Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom. Pathology Group, Blizard Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Farren
authors.affiliation: Department of Pathology, King's College University of London, London, United Kingdom.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
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: Xishan
authors.initials: X
authors.lastname: Hao
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Division of Haemato-Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom. liufengting@tjmuch.com s.g.agrawal@qmul.ac.uk.
authors.forename: Samir G
authors.initials: SG
authors.lastname: Agrawal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019927:Cyclin E; C508603:IL6R protein, human; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018809:Proliferating Cell Nuclear Antigen; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; C413374:p27 antigen; D051357:Cyclin-Dependent Kinase 2; C502936:tocilizumab