Τίτλος:
Chromatin structure, transcriptional activity and DNA repair efficiency
affect the outcome of chemotherapy in multiple myeloma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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<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<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.
Συγγραφείς:
Gkotzamanidou, M.
Sfikakis, P. P.
Kyrtopoulos, S. A.
Bamia,
C.
Dimopoulos, M. A.
Souliotis, V. L.
Περιοδικό:
British Journal of Cancer
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
multiple myeloma; melphalan; epigenetic changes; DNA damage response;
transcription-coupled repair; clinical outcome; malignant bone marrow
plasma cells; peripheral blood mononuclear cells
DOI:
10.1038/bjc.2014.410
