Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

Emerging evidence suggests the insulinlike growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R ␤-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G 2 /M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity.This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken IntroductionThe insulin-like growth factor-1 receptor (IGF-1R) is strongly suggested to play key roles in malignant transformation and in promoting survival of tumor cells from cancers of, for example, breast, prostate, and colon. 1,2 Also in multiple myeloma (MM) cells the IGF-1R has been shown by us and others to stimulate growth and potently mediate survival. [3][4][5][6][7][8][9][10][11] Some characteristic features of the MM disease include growth of tumor cells almost exclusively restricted to the bone marrow, complex genetic aberrations, the presence at a high frequency of illegitimate translocations of a few identified partner genes (ie, 11q13 [cyclin D1], 6p21 [cyclin D3], 4p16 [FGFR3/MMSET],, and 20q11 [mafB]) to the immunoglobulin heavy chain locus, and the altered expression of c-Myc and Bcl-2 family genes. 12 So far, genetic alterations of the IGF-1R in malignant cells, including MM, have not been reported. 13 However, in the bone marrow environment, the IGF-1R in MM cells may become hyperactive as a result of autocrine and/or paracrine stimulation, making molecules of the IGF-1R signaling pathway equally important targets for intervention as mutated oncogenes. Supporting the notion of the hyperactivated IGF-1R in MM is the recent finding that IGF-1 serum level is a prognostic factor in MM. 14 The fact that IGF-1R signaling seems not to be an absolute requirement for maintenance of normal cell homeostasis 13 would encourage the development of IGF-1R inhibitors for clinical use in MM, as they may not be associated with the severe side effects of conventional cytotoxic drugs.On ligand interaction with the IGF-1R ␣-subunit, tyrosine residues in the intracellular, membrane-bound ␤-subunit become autophosphorylated. 15 This enables docking and phosphorylation of the insulin receptor substrate (IRS) and Shc, thereby activating 2 important pathways mediating proliferation and survival, that is...

Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.