Genetic Modeling of PIM Proteins in Cancer: Proviral Tagging and Cooperation with Oncogenes, Tumor Suppressor Genes, and Carcinogens

Abstract

The PIM proteins, which were initially discovered as proviral insertion sites in Moloney-murine leukemia virus infection, are a family of highly homologous serine/threonine kinases that have been reported to be overexpressed in hematological malignancies and solid tumors. The PIM proteins have also been associated with metastasis and overall treatment responses and implicated in the regulation of apoptosis, metabolism, the cell cycle, and homing and migration, which makes these proteins interesting targets for anti-cancer drug discovery. The use of retroviral insertional mutagenesis and refined approaches such as complementation tagging has allowed the identification of myc, pim, and a third group of genes (including bmi1 and gfi1) as complementing genes in lymphomagenesis. Moreover, mouse modeling of human cancer has provided an understanding of the molecular pathways that are involved in tumor initiation and progression at the physiological level. In particular, genetically modified mice have allowed researchers to further elucidate the role of each of the Pim isoforms in various tumor types. PIM kinases have been identified as weak oncogenes because experimental overexpression in lymphoid tissue, prostate, and liver induces tumors at a relatively low incidence and with a long latency. However, very strong synergistic tumorigenicity between Pim1/2 and c-Myc and other oncogenes has been observed in lymphoid tissues. Mouse models have also been used to study whether the inhibition of specific PIM isoforms is required to prevent carcinogen-induced sarcomas, indicating that the absence of Pim2 and Pim3 greatly reduces sarcoma growth and bone invasion; the extent of this effect is similar to that observed in the absence of all three isoforms. This review will summarize some of the animal models that have been used to understand the isoform-specific contribution of PIM kinases to tumorigenesis.

The PIM family of oncoproteins: Small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets

“…PIM1 was originally identified as a common site of Moloney murine leukemia proviral insertion [4-6]. Subsequently, numerous studies have been focused on identifying the role of PIM1 in driving leukemogenesis.…”

“…The kinase family is composed of three members PIM1, PIM2 and PIM3, which are highly evolutionarily conserved in nearly all multicellular organisms. All three kinases are expressed in hematopoietic, neuronal, cardiomyocyte, endothelial, epithelial cell lineages and in embryonic stem cells [2, 4, 7-9]. In humans, PIM1 is located on chromosome 6, PIM2 on chromosome X and PIM3 on chromosome 22.…”

“…Previous studies have shown that PIM1 cooperates with c-MYC and n-MYC during lymphomagenesis [4, 12]. Moreover, PIM1 collaborates with BCL2, GFI1 and E2A-PBX1 to promote lymphomagenesis [2, 4].…”

“…Moreover, PIM1 collaborates with BCL2, GFI1 and E2A-PBX1 to promote lymphomagenesis [2, 4]. In cells lacking PIM1, activation of PIM2 through proviral insertion has been documented [13, 14].…”

“…pancreatic and prostate cancers, non-small-cell lung cancer, squamous cell carcinoma, gastric carcinoma, liver carcinoma, liposarcoma etc.) [2, 4, 17]. Dysregulation of these proto-oncogenes in human cancer is typically not due to gene alterations, mutations or amplifications, but occurs as a result of regulation at the transcriptional level.…”