title: Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas.
abstract: BACKGROUND
  A promising therapeutic approach for aggressive B-cell Non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL) is to target kinases involved in signal transduction and gene regulation. PIM1/2 serine/threonine kinases are highly expressed in activated B-cell-like DLBCL (ABC-DLBCL) with poor prognosis. In addition, both PIM kinases have a reported synergistic effect with c-MYC in mediating tumour development in several cancers, c-MYC gene being translocated to one of the immunoglobulin loci in nearly all BLs.
  
  
  METHODS
  For these reasons, we tested the efficiency of several PIM kinase inhibitors (AZD1208, SMI4a, PIM1/2 inhibitor VI and Quercetagetin) in preventing proliferation of aggressive NHL-derived cell lines and compared their efficiency with PIM1 and/or PIM2 knockdown.
  
  
  RESULTS
  We observed that most of the anti-proliferative potential of these inhibitors in NHL was due to an off-target effect. Interestingly, we present evidence of a kinase-independent function of PIM2 in regulating cell cycle. Moreover, combining AZD1208 treatment and PIM2 knockdown additively repressed cell proliferation.
  
  
  CONCLUSIONS
  Taken together, this study suggests that at least a part of PIM1/2 oncogenic potential could be independent of their kinase activity, justifying the limited anti-tumorigenic outcome of PIM-kinase inhibitors in NHL.
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. sarah_kreuz@gmx.net.
authors.forename: S
authors.initials: S
authors.lastname: Kreuz
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. medkho@leeds.ac.uk.
authors.forename: K B
authors.initials: KB
authors.lastname: Holmes
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. R.Tooze@leeds.ac.uk.
authors.forename: R M
authors.initials: RM
authors.lastname: Tooze
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, The Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK. p.lefevre@leeds.ac.uk.
authors.forename: P F
authors.initials: PF
authors.lastname: Lefevre
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: C587575:AZD1208; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D006657:Histones; C489427:MYC protein, human; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D053778:Thiazolidines; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1