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Updated: Jun 11, 2025
Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation
Published on: November 10, 2017
RNA kinetics influence the response to transcriptional perturbation in leukaemia cell lines
Izabela Todorovski1,2, Mary-Jane Tsang1,2, Breon Feran3,4
1Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
Abstract:
Therapeutic targeting of dysregulated transcription has emerged as a promising strategy for the treatment of cancers, such as leukaemias. The therapeutic response to small molecule inhibitors of Bromodomain-Containing Proteins (BRD), such as BRD2 and BRD4, P300/cAMP-response element binding protein (CBP) and Cyclin Dependent Kinases (CDKs), is generally attributed to the selective disruption of oncogenic gene expression driven by enhancers, super-enhancers (SEs) and lineage-specific transcription factors (TFs), including the c-MYC oncogene. The selectivity of compounds targeting the transcriptional machinery may be further shaped by post-transcriptional processes. To quantitatively assess the contribution of post-transcriptional regulation in responses to transcription inhibition, we performed multi-omics analyses to accurately measure mRNA production and decay kinetics. We demonstrate that it is not only the selective disruption of mRNA production, but rather mRNA decay rates that largely influence the selectivity associated with transcriptional inhibition. Accordingly, genes down-regulated with transcriptional inhibitors are largely characterized by extremely rapid mRNA production and turnover. In line with this notion, stabilization of the c-MYC transcript through swapping of its 3' untranslated region (UTR) rendered c-MYC insensitive to transcriptional targeting. This failed to negate the impact on c-MYC downstream targets and did not abrogate therapeutic responses. Finally, we provide evidence that modulating post-transcriptional pathways, such as through ELAVL1 targeting, can sensitize long-lived mRNAs to transcriptional inhibition and be considered as a combination therapy approach in leukaemia. Taken together, these data demonstrate that mRNA kinetics influence the therapeutic response to transcriptional perturbation and can be modulated for novel therapeutic outcomes using transcriptional agents in leukaemia.
Insights
mRNA decay rates, not just production, dictate cancer drug selectivity. Rapidly decaying genes are more sensitive to transcriptional inhibitors. Modulating mRNA turnover offers new therapeutic strategies for leukaemia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeting dysregulated transcription is a key cancer therapy strategy, particularly in leukaemias.
- Small molecule inhibitors targeting Bromodomain-Containing Proteins (BRD), P300/cAMP-response element binding protein (CBP), and Cyclin Dependent Kinases (CDKs) disrupt oncogenic gene expression.
- The selectivity of these inhibitors may be influenced by post-transcriptional processes.
Purpose of the Study:
- To quantitatively assess the role of post-transcriptional regulation in responses to transcription inhibition.
- To investigate how mRNA production and decay kinetics influence drug selectivity in cancer treatment.
- To explore novel therapeutic strategies by modulating mRNA turnover in leukaemias.
Main Methods:
- Multi-omics analyses were employed to measure mRNA production and decay kinetics.
- Quantitative assessment of mRNA turnover rates under transcriptional inhibition.
- Experiments involving 3' untranslated region (UTR) swapping of the c-MYC transcript.
- Investigation of ELAVL1 targeting to modulate post-transcriptional pathways.
Main Results:
- mRNA decay rates, rather than production rates alone, significantly influence the selectivity of transcriptional inhibitors.
- Genes downregulated by transcriptional inhibitors typically exhibit rapid mRNA production and turnover.
- Stabilizing the c-MYC transcript via 3' UTR modification rendered it insensitive to transcriptional targeting without abrogating therapeutic effects.
- Modulating post-transcriptional pathways, like ELAVL1, can sensitize long-lived mRNAs to transcriptional inhibition.
Conclusions:
- mRNA kinetics are critical determinants of therapeutic response to transcriptional perturbation in cancer.
- Post-transcriptional regulation, specifically mRNA decay, plays a major role in the selectivity of anti-cancer drugs targeting transcription.
- Targeting post-transcriptional pathways presents a viable combination therapy approach for leukaemias, enhancing the efficacy of transcriptional inhibitors.
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