Alternative Splicing in Chronic Myeloid Leukemia (CML): A Novel Therapeutic Target?
Patrick M. Pilarski,
Richard M. Stone,
James D. Griffin.
Although the imatinib based therapy of chronic myeloid leukemia (CML) represents a triumph of medicine, not
all patients with CML benefit from this drug due to the development of resistance and intolerance. The interruption of
imatinib treatment is often followed by clinical relapse, suggesting a failure in the killing of residual leukaemic stem cells.
There is need to identify alternative selective molecular targets for this disease and develop more effective therapeutic
approaches. Alternative pre-mRNA splicing (AS) is an epigenetic process that greatly diversifies the repertoire of the
transcriptome. AS orchestrates interactions between various types of proteins and between proteins and nucleic acids.
Changes caused by individual splicing events in the cells are small, however, “splicing programs” typically react to these
individual changes with considerable effects in cell proliferation, cell survival, and apoptosis. Current evidence suggests a
pivotal role of AS in leukemias, particularly in myelodisplastic syndrome (MDS) and chronic lymphocyte leukemia
(CLL). From these studies and studies in other malignances, it is clear that splicing abnormalities play a significant role in
malignant transformation. Evaluation of AS events in CML can be used to identify novel disease markers and drugsensitive
targets to overcome the limits of the small molecule inhibitors currently used for treating patients with CML.
The use of aberrant splice variants as disease markers has been reported, however, little is known about the use of splicing
abnormalities as drug targets in CML. Herein we discuss potential therapeutic approaches that can be used to target
splicing abnormalities in CML.
Keywords: Alternative splicing, BCR-ABL, bio-markers, chronic myeloid leukemia, therapeutic targets.
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