PIM2 inhibition as a rational therapeutic approach in B-cell lymphoma

Blood. 2011 Nov 17;118(20):5517-27. doi: 10.1182/blood-2011-03-344374. Epub 2011 Sep 21.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Biomarkers, Tumor / metabolism
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / genetics
  • Genetic Therapy / methods*
  • Humans
  • Lymph Nodes / pathology
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / pathology
  • Lymphoma, Follicular / therapy
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Mantle-Cell / genetics
  • Lymphoma, Mantle-Cell / pathology
  • Lymphoma, Mantle-Cell / therapy
  • Palatine Tonsil / pathology
  • Phosphoproteins / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • bcl-Associated Death Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BAD protein, human
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Enzyme Inhibitors
  • PIM2 protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • bcl-Associated Death Protein
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt