@article {7438,
	title = {DNA repair of myeloma plasma cells correlates with clinical outcome: The effect of the nonhomologous end-joining inhibitor SCR7},
	journal = {Blood},
	volume = {128},
	year = {2016},
	note = {Export Date: 21 February 2017},
	month = {2016},
	pages = {1214 - 1225},
	abstract = {DNA repair activity of malignant cells seems to influence therapeutic outcome and patients{\textquoteright} survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n = 17) or did not respond (n = 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders{\textquoteright} BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders{\textquoteright} cells compared with those of nonresponders (P = .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates ofDSB/R and increasedmelphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders{\textquoteright} BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs andDSBs lesions,which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. {\textcopyright} 2016 by The American Society of Hematology.},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84987600756\&doi=10.1182\%2fblood-2016-01-691618\&partnerID=40\&md5=02603e02b5e983e079d603b495133470},
	author = {Gkotzamanidou, M. and Terpos, E. and Bamia, C. and Munshi, N.C. and Dimopoulos, M.A. and Souliotis, V.L.}
}
