Alteration of Pim-2 expression by clinically available anti-myeloma agents: combinatory anti-myeloma effects with Pim inhibition

Abstract

panel of 84 DNA damage response-related genes were measured. Results: The accumulation of melphalan-induced monoadducts was inversely correlated with the first-phase repair capacity of cells, being significantly higher in HC than in responders and lowest in non-responders (all P<0.001). In addition, the accumulation of ICLs was significantly higher in HC compared to responders (P<0.01), due to higher levels of monoadducts (precursors of ICLs) left unrepaired in these cells. Minimal amounts of ICLs were observed in non-responders. Moreover, DSBs burden was significantly higher in HC than in responders, due to higher accumulation of ICLs (precursors of DSBs) and lower rates of DSB repair in these cells (P<0.01). Minimal amounts of ICLs were observed in non-responders. More interestingly, apoptotic rates were inversely correlated with the DSBs repair efficiency being significantly higher in HC compared to responders and lowest in non-responders (all P<0.05). PBMCs without exposure to melphalan, showed a progressive and significant increase in the looseness of the local chromatin structure, from HC to MM-responders and finally to non-responders (all P<0,05). To note, microarray analysis of untreated PBMCs consistently points to an altered expression of several DNA damage response-related genes in MM patients. Responders showed significant upregulation of ATR, CHEK2, XPA, XRCC1 and CHEK2 genes and downregulation of ATM, MPG, UNG, CDKN1A and CDC25C compared to non-responders. Conclusion: MM patients with deficient DNA repair pathways exhibit simultaneous accumulation of the extremely cytotoxic ICLs and DSBs lesions, which in turn triggers the induction of the apoptotic pathway, a priority for successful clinical outcome.