The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

Abstract

Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFa, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-jB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.

Pinning down myeloma with Pim2 inhibitors!

“…Furthermore, and consistent with an additive rather than epistatic effect on TSC2, the previous work by Asano et al 6 reported that treatment with the Pim2 inhibitor and LY294002 (PI3K inhibitor) cooperatively suppressed MM cells viability.…”

“…6,7 By counteracting the methylated status of H3K4, Jarid1b would shift the balance toward repression of these genes, and conversely its knockdown would favor gene activation (see figure). This is obviously a highly simplistic model.…”

“…4 Of these, only 7 mutated amino acid sites remained problematic for selecting a presumably effective "next-line" TKI. 5,6 One of the open clinical questions is why some resistant patients with 1 or more of the 7 mutations do not respond even though rationally selecting treatment according to in vitro and in vivo experiences. European LeukemiaNet recommendations have been published for how best to identify BCR-ABL mutations in case of unsatisfying response or frank failure on TKI treatment.…”

Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma

“…[44][45][46][47] Pim kinases, particularly Pim-2, are known to be downstream of B-lymphocyte stimulator and NF-B, and are both regulator and target of STAT3. [48][49][50] All of these pathways interconnect, and it is reasonable to postulate potential overlap and interactions between Pim kinases and these growth or transcription factors.…”

AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

“…[3][4][5][6] In AML, this is driven at least in part by activation of receptor tyrosine kinases such as the Flt3-internal tandem duplication (Flt3-ITD) mutation 5,7,8 found in approximately one third of AML patients. The JAK/STAT pathway, a key mediator of cytokine and growth factor signaling, plays an important role in regulating Pim expression.…”