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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Apoptosis / physiology
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Biomarkers, Tumor / metabolism
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Cell Cycle Proteins
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Neoplastic / genetics
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Genetic Therapy / methods*
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Humans
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Lymph Nodes / pathology
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Lymphoma, Follicular / genetics
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Lymphoma, Follicular / pathology
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Lymphoma, Follicular / therapy
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Lymphoma, Large B-Cell, Diffuse / drug therapy*
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Lymphoma, Large B-Cell, Diffuse / genetics*
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Lymphoma, Large B-Cell, Diffuse / pathology
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / pathology
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Lymphoma, Mantle-Cell / therapy
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Palatine Tonsil / pathology
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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bcl-Associated Death Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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BAD protein, human
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Biomarkers, Tumor
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Enzyme Inhibitors
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PIM2 protein, human
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Phosphoproteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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bcl-Associated Death Protein
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt