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

Abstract

PIM kinases are a family of serine/threonine kinases involved in cell survival and proliferation. There is significant structural similarity between the three PIM kinases (PIM1, PIM2 and PIM3) and few amino acid differences. Although, several studies have specifically monitored the role of PIM1 in tumorigenesis, much less is known about PIM2 and PIM3. Therefore, in this study we have used in vitro cell culture models and in vivo bone marrow infection/transplantation to assess the comparative signaling and oncogenic potential of each of the three PIM kinases. All three PIM kinases were able to protect FL5.12 cells from IL-3 withdrawal induced death. Interestingly, the downstream signaling cascades were indistinguishable between the three kinases. Transplantation of murine bone marrow co-expressing MYC and PIM1, PIM2 or PIM3 caused rapid and uniformly lethal myeloid leukemia. De-induction of MYC 18 days following transplantation significantly increased the survival of mice, even with continual expression of PIM kinases. Alternatively, mice treated at the pre-leukemic stage with a PIM kinase inhibitor increased the lifespan of the mice, even with continual expression of the MYC transgene. These data demonstrate the role of PIM kinases in driving myeloid leukemia, and as candidate molecules for therapy against human malignancies.

Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

“…This is interesting because a role for Pim1 kinase has not been previously linked to HTLV-I or ATL-transformed cells, although it has been implicated in other leukemias. 20 We confirmed loss of Pim1 protein expression in tumors from ED-40515(-) TET-mIR-124a mice ( Figure 4C-D) and the suppressive effects of miR-124a on Pim1 in vitro, TET-miR-124a ATL lines ED-40515(-), and Tl-Om1 ( Figure 4E). Pim1 loss was accompanied by decreased phosphorylation of substrates, Bcl-2, 4E-BP1, and p70S6 Kinase, and decreased expression of SOCS3, a target of Pim1 regulation ( Figure 4F).…”

Effects of low doses of Tat-PIM2 protein against hippocampal neuronal cell survival

“…HT22 cells [3,5,47,48]. On the contrary, our data demonstrated that low doses of Tat-PIM2 protein significantly protected H 2 O 2 -induced cell death in HT22 cells.…”

“…PIM2 was identified as the site of viral insertion in retrovirally induced murine leukemia [1][2][3]. Several studies have demonstrated that PIM2 promotes cell survival by regulation of growth factor signaling, phosphorylation of BAD, NF-κB signaling [39][40][41][42][43][44].…”

“…The PIM proteins are highly conserved in multicellular homologous organisms [1][2][3]. PIM2 was first discovered in lymphomas in mice and found to have anti-apoptotic effects as well as several other functions including cell cycle regulation, cell proliferation, and transcriptional activity [2,[4][5][6][7][8].…”

The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks

“…Therefore, its downregulation by hesperetin could be a strategy to inhibit HL60 cell growth. PIM1, a member of serine/threonine kinases involved in cell survival and proliferation, is overexpressed in a variety of cancer types such as leukemias, lymphomas, and pancreatic and prostate cancers [44]. It is also known that PIM1 functions together with C-MYC to induce malignancy.…”