title: PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma.
abstract: PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
authors.affiliation: Molecular Pathology Programme, Lymphoma Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gómez-Abad
authors.forename: Helena
authors.initials: H
authors.lastname: Pisonero
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Roncador
authors.forename: Alberto
authors.initials: A
authors.lastname: González-Menchén
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
authors.forename: Eva
authors.initials: E
authors.lastname: Mata
authors.forename: María Elena
authors.initials: ME
authors.lastname: Rodríguez
authors.forename: Guillermo
authors.initials: G
authors.lastname: Muñoz-González
authors.forename: Margarita
authors.initials: M
authors.lastname: Sánchez-Beato
authors.forename: Juan F
authors.initials: JF
authors.lastname: Leal
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy; D014066:Palatine Tonsil / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494819:BAD protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; C490587:PIM2 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt