Pim2 Gene Editing

The proviral integration site for Moloney murine leukemia virus 2 (PIM2) is a type of serine/threonine kinase belonging to the PIM family, which plays an important role in cellular proliferation, survival and differentiation. PIM2 exists on the X chromosome in three isotypes and is highly expressed in lymphatic and brain tissues.

Transcription Factors Responsible for PIM2 Gene Activation

The transcriptional regulation of PIM2 expression is a complex and sophisticated process, which can be influenced by many signaling factors, including interleukins, GCSF, GM-CSF, and interferons. Most of these factors have their primary signals transformed by the JAΚ/STAT pathway. Cytokines bind to cell surface receptors that activate the JAΚ/STAT pathway, and the activation of STAT through JAΚ phosphorylation results in dimerization and nuclear translocation. In the nucleus, these dimers regulate the gene expression by binding to target-specific gene promoter regions: STAT3 and STAT5 bind directly to the PIM2 promoter at the ISFR/GAS-sequence to up-regulate gene expression. Transcription factors downstream of this growth factor signaling pathway, such as NFκB, can also regulate its expression, because PIM2 has been shown to be up-regulated by NFκB in response to FLT3/ITB oncogenic mutants. The effect of PIM2 on cell survival depends on the activation of the NFκB pathway, which acts as an important mediator. PIM2 activates NFκB-dependent gene expression by inducing the phosphorylation of serine threonine kinases, resulting in an increase in IκB kinase activation, and a shift in nuclear NFκB from predominantly P50 homodimers to P50/P65 heterodimers. Studies have shown that PIM2 may exert certain immune regulation effects. Yang et al. proved that PIM2 can induce interleukin (IL)-6 production through the IL-1β or TNF-α pathway, thereby regulating the occurrence of inflammatory diseases.

Pim2 Gene Editing Figure 1. Transcription factors responsible for PIM2 gene transcription. (Wang Y, et al. 2021)

Pim2 and Cancer

At present, most studies on PIM2 focus on its role in hematological malignancies and solid tumors, and it has been revealed that PIM2 can promote the occurrence and development of multiple myeloma, liver cancer, prostate cancer, and other tumors, including ovarian cancer, lung cancer. PIM2 is mainly expressed in both leukemia and solid tumors, and it promotes the transcriptional activation of genes involved in cell survival, cell proliferation, and cell-cycle progression. Many tumorigenic signaling molecules have been identified as substrates for PIM2 kinase, and various inhibitors have been developed for its kinase activity, including SMI-4a, SMI-16a, JP11646, SGI-1776, and DHPCC-9.

PIM2 was specifically upregulated in acute myeloid leukemia (AML) and plasma cell dyscrasia multiple myeloma (MM). In myeloma, stromally-derived factors like IL-6 or the TNF family of cytokines, through NFκB signaling regulate PIM2 and its key role in MM cell survival and adaptation to stress (e.g. to chemotherapy treatment). This is in part mediated by PIM2 phosphorylation of its downstream targets TSC2, the proapoptotic factor BAD and the protein translational inhibitor 4EBP1. PIM2 also participates in the myeloma-mediated bone destruction through negative regulation of osteoblastogenesis and more recently in the regulation of the essential DNA damage response pathway in myeloma. These observations indicate that therapeutically targeting PIM2 may have significant efficacy in MM. In preclinical studies, the PIM2 selective inhibitor LGB321 has been shown to induce MM cell death by inhibiting mTORC1 activity, and in a phase I MM trial the pan-PIM inhibitor LGH447 had acceptable toxicity with evidence for clinical efficacy.