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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
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RaRF confers RA resistance by sequestering RAR to the nucleolus and regulating MCL1 in leukemia cells
1Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea.
Oncogene
|September 26, 2017
Summary
A novel repressor, RA resistance factor (RaRF), causes resistance to retinoic acid (RA) cancer therapy by blocking the RA receptor. Depleting RaRF restores RA sensitivity and promotes leukemia cell differentiation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Retinoic acid (RA) is a crucial therapy for acute promyelocytic leukemia (APL) and other cancers.
- Therapeutic limitations include patient relapse due to poorly understood mechanisms of RA resistance.
Purpose of the Study:
- To elucidate a novel molecular mechanism underlying retinoic acid resistance in cancer.
- To identify RA resistance factor (RaRF) as a potential therapeutic target for overcoming RA resistance.
Main Methods:
- Investigated the interaction between RaRF and the retinoic acid receptor (RAR).
- Assessed the effect of RaRF expression on transcriptional activity and cellular localization of RAR.
- Correlated RaRF expression levels with RA sensitivity in leukemia cells.
- Examined the impact of RaRF depletion on MCL1 expression and leukemic myeloblast differentiation.
Main Results:
- Identified RaRF as a repressor that binds to RAR and sequesters it in the nucleolus, inhibiting its transcriptional activity in response to RA.
- Demonstrated high expression of RaRF in RA-resistant leukemia cells, with expression levels inversely correlated to RA sensitivity.
- Showed that RaRF depletion leads to MCL1 upregulation and promotes leukemic myeloblast differentiation upon RA treatment.
- Confirmed that ectopic RaRF expression negatively regulates leukemic myeloblast differentiation.
Conclusions:
- RaRF represents a novel molecular mechanism contributing to RA resistance in cancer therapy.
- RaRF's role in inhibiting RAR activity and blocking differentiation makes it a potential therapeutic target for overcoming RA resistance in leukemia.
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