Abstract
Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.
Original language | English (US) |
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Pages (from-to) | 80-94 |
Number of pages | 15 |
Journal | British Journal of Haematology |
Volume | 177 |
Issue number | 1 |
DOIs | |
State | Published - Apr 1 2017 |
Keywords
- multiple myeloma
- myeloma cell lines
- myeloma therapy
- oncogenes
ASJC Scopus subject areas
- Hematology