TY - JOUR
T1 - Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a Cereblon-independent manner
AU - Dimopoulos, Konstantinos
AU - Søgaard Helbo, Alexandra
AU - Fibiger Munch-Petersen, Helga
AU - Sjö, Lene
AU - Christensen, Jesper
AU - Sommer Kristensen, Lasse
AU - Asmar, Fazila
AU - Hermansen, Emil
AU - O'Connel, Casey
AU - Gimsing, Peter
AU - Liang, Gangning
AU - Grønbaek, Kirsten
N1 - Molecular Oncology (2017) © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2017
Y1 - 2017
N2 - Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide- (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance. By assessing genome-wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD-resistance is associated with an increase of genome-wide DNA methylation and an even greater reduction of chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes are potentially reversible, since combination of 5-Azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl-transferases (DNMTs) and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.
AB - Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide- (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance. By assessing genome-wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD-resistance is associated with an increase of genome-wide DNA methylation and an even greater reduction of chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes are potentially reversible, since combination of 5-Azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl-transferases (DNMTs) and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.
KW - Journal Article
U2 - 10.1002/1878-0261.12157
DO - 10.1002/1878-0261.12157
M3 - Journal article
C2 - 29130642
SN - 1574-7891
VL - 12
SP - 180
EP - 195
JO - Molecular Oncology
JF - Molecular Oncology
IS - 2
ER -