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Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner

Authors :
Fazila Asmar
Casey O'Connel
Lasse Sommer Kristensen
Gangning Liang
Peter Gimsing
Helga Fibiger Munch-Petersen
Kirsten Grønbæk
Konstantinos Dimopoulos
Niels Emil Ulrich Hermansen
Alexandra Søgaard Helbo
Jesper Christensen
Lene Dissing Sjö
Source :
Dimopoulos, K, Søgaard Helbo, A, Fibiger Munch-Petersen, H, Sjö, L, Christensen, J, Sommer Kristensen, L, Asmar, F, Hermansen, N E U, O'Connel, C, Gimsing, P, Liang, G & Grønbaek, K 2018, ' Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner ', Molecular Oncology, vol. 12, no. 2, pp. 180-195 . https://doi.org/10.1002/1878-0261.12157, Molecular Oncology, Molecular Oncology, Vol 12, Iss 2, Pp 180-195 (2018), Dimopoulos, K, Søgaard Helbo, A, Fibiger Munch-Petersen, H, Sjö, L, Christensen, J, Sommer Kristensen, L, Asmar, F, Hermansen, N E U, O'Connel, C, Gimsing, P, Liang, G & Grønbaek, K 2018, ' Dual inhibition of DNMTs and EZH2 can overcome both intrinsic and acquired resistance of myeloma cells to IMiDs in a cereblon-independent manner ', Molecular Oncology, vol. 12, no. 2 . https://doi.org/10.1002/1878-0261.12157
Publication Year :
2017
Publisher :
Wiley, 2017.

Abstract

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.

Details

ISSN :
15747891
Volume :
12
Database :
OpenAIRE
Journal :
Molecular Oncology
Accession number :
edsair.doi.dedup.....e83dac78444f1a137d42b38da96d302e