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A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
Published on: December 4, 2018
Chronic myelogenous leukemia on target
Veronika Némethová1, Filip Rázga1
1Department for Biomaterials Research, Polymer Institute of the Slovak Academy of Sciences, Bratislava, Slovakia.
Abstract:
Chronic myelogenous leukemia (CML) is commonly treated with tyrosine kinase inhibitors (TKIs) that inhibit the pro-leukemic activity of the BCR-ABL1 oncoprotein. Despite the therapeutic progress mediated by TKI use, off-target effects, treatment-induced drug resistance, and the limited effect of these drugs on CML stem cells (SCs) are major drawbacks frequently resulting in insufficient or unsustainable treatment. Therefore, intense research efforts have focused on development of improved TKIs and alternative treatment strategies to eradicate CML SCs. Alongside efforts to design superior protein inhibitors, the need to overcome the poor therapeutic effect of TKIs on CML SCs has led to a renaissance of antisense strategies, as they are reported as effective in more primitive cell types. Despite the greater drug design flexibility offered by antisense sequence variability and remarkable chemical improvements, antisense drugs exhibit unacceptable levels of off-target effects, precluding them from large-scale clinical testing. Recent advances in antisense drug design have led to a pioneering mRNA recognition concept that may offer a helping hand in eliminating off-target effects, and has potential to bridge the gap between research and clinical practice.
Insights
New antisense strategies show promise for treating chronic myelogenous leukemia (CML) by targeting CML stem cells. Advances in mRNA recognition may reduce off-target effects, improving treatment efficacy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Chronic myelogenous leukemia (CML) is often treated with tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein.
- TKIs face challenges including off-target effects, drug resistance, and limited efficacy against CML stem cells (SCs).
- Eradicating CML SCs is crucial for achieving sustainable treatment outcomes.
Purpose of the Study:
- To explore alternative treatment strategies for CML, focusing on overcoming TKI limitations.
- To investigate the potential of antisense strategies for targeting CML stem cells.
- To address and mitigate off-target effects associated with antisense therapies.
Main Methods:
- Review of current TKI limitations in CML treatment.
- Exploration of antisense strategies as an alternative therapeutic approach.
- Examination of recent advances in antisense drug design, including mRNA recognition concepts.
Main Results:
- Antisense strategies show potential for targeting primitive CML cell types, including SCs.
- Current antisense drugs face significant challenges with off-target effects.
- Novel mRNA recognition concepts offer a potential solution to reduce off-target effects.
Conclusions:
- Antisense strategies represent a promising avenue for CML treatment, particularly for eradicating CML SCs.
- Advances in mRNA recognition are critical for developing safer and more effective antisense therapies.
- The development of targeted antisense drugs could bridge the gap between preclinical research and clinical application in CML therapy.
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