Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

Manoj K Kashyap; Deepak Kumar; Reymundo Villa; James J La Clair; Chris Benner; Roman Sasik; Harrison Jones; Emanuela M Ghia; Laura Z Rassenti; Thomas J Kipps; Michael D Burkart; Januario E Castro

doi:10.3324/haematol.2014.122069

Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

Haematologica. 2015 Jul;100(7):945-54. doi: 10.3324/haematol.2014.122069. Epub 2015 Apr 10.

Authors

Affiliations

¹ Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
² Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
³ Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁴ Center for Computational Biology, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.
⁵ Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA CLL Research Consortium, and Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁶ Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA CLL Research Consortium, and Department of Medicine, University of California, San Diego, La Jolla, CA, USA [email protected] [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Epoxy Compounds / pharmacology*
Gene Expression
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Macrolides / pharmacology*
Mice
Mice, Inbred BALB C
Mutation
Phosphoproteins / genetics
Phosphoproteins / metabolism
RNA Splicing / drug effects
RNA Splicing Factors
RNA, Messenger / antagonists & inhibitors*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Ribonucleoprotein, U2 Small Nuclear / genetics
Ribonucleoprotein, U2 Small Nuclear / metabolism
Spliceosomes / drug effects*
Survival Analysis
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

Anti-Bacterial Agents
Antineoplastic Agents
Epoxy Compounds
FD 895
Macrolides
Phosphoproteins
RNA Splicing Factors
RNA, Messenger
Ribonucleoprotein, U2 Small Nuclear
SF3B1 protein, human
TP53 protein, human
Tumor Suppressor Protein p53
pladienolide B

Abstract

Publication types

MeSH terms

Substances

Grants and funding