Most experimental data has been generated using PIM1; very little is known about regulation of PIM2 and PIM3. aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we spotlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. gene locus was mapped to mouse chromosome 17, and to short arm of chromosome 6 (6p21) in the human genome. Further analysis revealed that this open reading frame of PIM1 encoded for a protein of 313aa extending over 6 exons, with highest homology to serine/threonine kinases.2 Predisposition to lymphomagenesis in PIM1 transgenic mice through cooperation with c-myc and N-myc demonstrated the proto-oncogenic activity of PIM1.3 Subsequent studies have characterized PIM1 as synergizing oncogene with over-expressed BCL2, GFI1, loss of FAS-L, or in collaboration of a leuke-mogenic fusion gene (gene encodes for two isoforms of 34 and 44kD through the use of alternative initiation sites. Both isoforms contain the kinase domain name and exhibited comparable kinase activity.5 PIM1 was found ubiquitously expressed and to function as a protein with a short half-life. Interestingly, the half-life of PIM1 ( 5 min) observed in normal peripheral leukocytes was significantly increased in K562, a Philadelphia chromosome-positive leukemia cell line derived from chronic myeloid leukemia in blast crisis.6 Abundant levels of MGC57564 PIM1 were AX-024 found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or IL-6.7 Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFN, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels (Determine 1). Other studies have shown that PIM1 kinase is usually significantly guarded from proteasomal degradation by heat shock proteins (Hsp70, Hsp90).8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression.10,11 Open in a separate window Determine 1. Regulation of PIM1 expression. Binding of several ligands leads to activation of a AX-024 complex network of signaling pathways that results in upregulation of PIM1 mRNA. Binding of PIM1 to heat shock protein 90 (HSP90) protects from proteosomal degradation. Most experimental data has been generated using PIM1; very little is known about regulation of PIM2 and PIM3. There is increasing evidence for modification of PIM kinases through as yet unkown protein kinases and/or phosphatases. Germline inactivation of the gene was associated AX-024 with a moderate phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1?/? mice showed erythrocytic microcytosis and PIM1?/? B cells and bone marrow-derived mast cells were impaired in interleukin-7 (IL-7) or IL-3 induced proliferation.12,13 Retroviral insertion site cloning in secondary transplants of Moloney murine computer virus induced lymphomas revealed PIM2 as a frequent but late event in tumorigenesis.14 Interestingly, proviral tagging in transgenic mice lacking PIM1 has led to compensatory activation of PIM2. The gene located on chromosome Xp11 comprises 6 exons and is 53% identical to PIM1 at the amino acid level and shares preference and usage of non-AUG alternative initiation codons leading to 3 different isoforms. PIM2 is usually ubiquitously expressed with highest levels in brain and lymphoid cells, and like PIM1, PIM2 also potently synergizes in c-MYC induced lymphomagenesis. 15 Through high throughput retroviral tagging in tumors of transgenic mice lacking PIM1 and PIM2, Mikkers and colleagues found selective activation of PIM3 suggesting that PIM3 can substitute for PIM1 and PIM2 in MuLV-induced lymphomagenesis.16 The gene is located on chromosome 22q and encodes for a serine/threonine kinase with over 60% homology to PIM1 and PIM2, that is ubiquitously expressed with highest levels in kidney, breast and brain.17 PIM1, PIM2 and PIM3 compound knockout mice that survived the perinatal period displayed a profound reduction in body size suggesting that PIMs are important for body growth. Colony forming assays with bone marrow from PIM1?/?PIM2?/?PIM3?/? mice exhibited that PIMs act redundantly in clonogenic growth in response to IL-3, IL-5, SCF and TPO. However, PIM1 seems to be the most crucial isoform for.