Figure 2.

Pim signaling in MM. Pim-2 is upregulated in MM. BMSCs, present in the microenvironment secrete IL-6 (depicted in grey) and increase Pim-2 transcription via STAT3 signaling. OCs release tumor necrosis factor family members TNFα, BAFF and APRIL (depicted in green), which then act via NFκB to increase Pim-2 transcription. Pim-2 has a role in prevention of apoptosis by phosphorylating MDM2 and reducing the degradation of p53, phosphorylation of ASK-1 and phosphorylation of the pro-apoptotic BAD at serine 112. This latter effect on BAD is shared with the PI3K/AKT/mTOR pathway also important in MM. These two pathways also converge on mTOR signaling. Pim-2 phosphorylates TSC2 to release the inhibitory effect of Rheb on mTORC1. Akt phosphorylates PRAS40 to activate mTORC1. Downstream of mTOR activation, both cap-dependent and cap-independent translation is initiated. The ribosomal proteins 4EBP1 and S6 kinase are phosphorylated to initiate cap-independent translation. Following phosphorylation of 4EBP1, eIF4E is released and forms a translation initiation complex with eIF4A, eIF4G and eIF3. The ribosomal 40S subunit can then bind to ‘weak' mRNA transcripts which contain a GC-rich region and capped by 7-methylguanosine. Among the pro-myeloma proteins translated in this manner are MYC, cyclin D1, MCL-1 and the Pim kinases themselves. This forms part of the oncogenic collaboration between the Pims and MYC. The Pims cannot perform oncogenic functions in the absence of MYC expression,³⁹ and in turn, the Pims phosphorylate and stabilize MYC.⁴⁰ Pims complex with MYC and MAX and are recruited to the E-box of MYC where Pims phosphorylate serine10 of histone 3 (H3S10) to induce transcription of up to 20% of MYC target genes.⁴¹ A putative role for the Pim kinases in MM, as has been demonstrated in other hematologic malignancies, is phosphorylation of CXCR4 on serine 339 with resultant internalization and re-expression of CXCR4, facilitating homing and migration.