Targeting the IGF-1R signaling and mechanisms for epigenetic gene silencing in human multiple myeloma

Abstract

Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell-cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM.

Figure 1.

The most prominent ligand-receptor interactions with superior affinity over other ligands, i.e. IGF-1 to the IGF-1R and hybrids with either IR-A or IR-B, IGF-2 binds with high affinity IGF-1R, IR-A, and heterodimers with this isoform, while insulin displays high affinity for the IR and splice variants IR-A and IR-B only.

Figure 2.

The H3K27me3 target genes defined by Bracken et al. (81) in embryonic fibroblasts are statistically associated to underexpressed genes in MM and MGUS using the data-mining platform Oncomine. A: The top 10% underexpressed genes in MM patients (compared to normal bone-marrow) show a strong connection to genes previously described as H3K27me3 targets in human embryonic fibroblasts. B: The H3K27me3 target genes were also overrepresented among genes underexpressed in MGUS patients, and (C) strongly associated with decreased expression in ISS stage III MM, compared to stage I and II. D: The PRC2 targets CIITA, GATA2, CDH6, CXCL12, and ICSBP/IRF8 are underexpressed in MM. From Kalushkova et al. (10) with permission.

Figure 3.

A: In a preclinical setting a few selected candidate target genes from the integrative genomic analysis were analyzed and found to be reactivated by chemical inhibitors in MM cell lines in vitro. B: Treatment with LBH589 significantly reduced tumor load in the 5T3MM mouse model, and also increased overall survival in this model (C). From Kalushkova et al. (10) with permission.