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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B
Manoj K Kashyap1, Deepak Kumar1, Reymundo Villa2
1Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Abstract:
RNA splicing plays a fundamental role in human biology. Its relevance in cancer is rapidly emerging as demonstrated by spliceosome mutations that determine the prognosis of patients with hematologic malignancies. We report studies using FD-895 and pladienolide-B in primary leukemia cells derived from patients with chronic lymphocytic leukemia and leukemia-lymphoma cell lines. We found that FD-895 and pladienolide-B induce an early pattern of mRNA intron retention - spliceosome modulation. This process was associated with apoptosis preferentially in cancer cells as compared to normal lymphocytes. The pro-apoptotic activity of these compounds was observed regardless of poor prognostic factors such as Del(17p), TP53 or SF3B1 mutations and was able to overcome the protective effect of culture conditions that resemble the tumor microenvironment. In addition, the activity of these compounds was observed not only in vitro but also in vivo using the A20 lymphoma murine model. Overall, these findings give evidence for the first time that spliceosome modulation is a valid target in chronic lymphocytic leukemia and provide an additional rationale for the development of spliceosome modulators for cancer therapy.
Insights
New cancer drugs FD-895 and pladienolide-B target RNA splicing in leukemia cells. These spliceosome modulators induce cancer cell death, showing promise for treating chronic lymphocytic leukemia.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- RNA splicing is crucial in human biology.
- Spliceosome mutations impact cancer patient prognosis, especially in hematologic malignancies.
Purpose of the Study:
- To investigate the therapeutic potential of spliceosome modulators FD-895 and pladienolide-B in chronic lymphocytic leukemia (CLL).
- To determine if spliceosome modulation can overcome cancer cell resistance mechanisms.
Main Methods:
- Treatment of primary CLL cells and leukemia-lymphoma cell lines with FD-895 and pladienolide-B.
- Analysis of mRNA intron retention as a marker of spliceosome modulation.
- Assessment of apoptosis in cancer cells versus normal lymphocytes.
- In vitro and in vivo studies using the A20 lymphoma murine model.
Main Results:
- FD-895 and pladienolide-B induced mRNA intron retention (spliceosome modulation).
- These compounds selectively triggered apoptosis in cancer cells, irrespective of poor prognostic markers (Del(17p), TP53, SF3B1 mutations).
- Activity was confirmed both in vitro and in vivo, overcoming tumor microenvironment protective effects.
Conclusions:
- Spliceosome modulation is a viable therapeutic target for chronic lymphocytic leukemia.
- FD-895 and pladienolide-B demonstrate significant anti-leukemic activity, supporting their development as novel cancer therapies.
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