Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma
Authors: M A Dimopoulos
V L Souliotis
S A Kyrtopoulos
P P Sfikakis
M Gkotzamanidou
C Bamia
Journal: British Journal of Cancer (2014)
Discipline: CLINICAL MEDICINE
Keywords: Melphalan; multiple myeloma; chromatin structure; transcriptional activity; DNA damage response
Affiliations: 1] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA [2] Department of Clinical Therapeutics, University of Athens School of Medicine, 11528 Athens, Greece., First Department of Propedeutic Medicine, University of Athens School of Medicine, 11527 Athens, Greece., Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece., Department of Hygiene, Epidemiology and Medical Statistics, University of Athens School of Medicine, 11527 Athens, Greece., Department of Clinical Therapeutics, University of Athens School of Medicine, 11528 Athens, Greece.

Abstract:  Background: Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown. Methods: Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study. Results: In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P&lt;0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P&lt;0.001). Conclusions: Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy. 

Retracted: No

PubPeer comments:
 **RETRACTION**  After publication of the Report u201c**Site-selective enzymatic Cu2014H amidation for synthesis of diverse lactamsu201d** (1), efforts to reproduce the work showed that the enzymes do not catalyze the reactions with the activities and selectivities claimed. Careful examination of the first author s lab notebook then revealed missing contemporaneous entries and raw data for key experiments. **The authors are therefore retracting the paper**. Authors: Inha Cho, Zhi-Jun Jia, Frances H. Arnold Science 10 Jan 2020: Vol. 367, Issue 6474, pp. 155 DOI: 10.1126 science.aba6100 https: science.sciencemag.org content 367 6474 155.1.full , 
 Retraction Watch **Nobel winner retracts paper from Science** https: retractionwatch.com 2020 01 02 nobel-winner-retracts-paper-from-science ,