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Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with

Jun Liu1, Malini Bhadra1, Joanna Rajeswary Sinnakannu2

  • 1School of Biological Sciences, Nanyang Technological University, Singapore.

Oncotarget
|November 5, 2017
PubMed

Insights

Researchers developed splice-switching antisense oligonucleotides (ASOs) to overcome imatinib resistance in chronic myeloid leukemia (CML) caused by BIM gene splicing defects. These ASOs restored sensitivity to tyrosine kinase inhibitors (TKIs) in resistant cancer cells.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Tyrosine kinase inhibitors (TKIs) like imatinib are effective against many cancers, including chronic myeloid leukemia (CML).
  • A specific BIM gene deletion polymorphism in East Asians causes primary imatinib resistance by disrupting TKI-induced apoptosis.
  • This polymorphism leads to aberrant BIM splicing, omitting the pro-apoptotic BH3 domain and reducing TKI efficacy.

Purpose of the Study:

  • To identify splice-switching antisense oligonucleotides (ASOs) that correct aberrant BIM splicing.
  • To resensitize BIM deletion-containing cancer cells to imatinib by restoring proper BIM splicing.
  • To provide a proof-of-principle for ASO-based therapy in TKI-resistant cancers.

Main Methods:

  • Minigene assays were used to map cis-acting splicing elements around BIM exon 3, identifying an exonic splicing enhancer involving SRSF1.
  • A systematic antisense oligonucleotide (ASO) screen was conducted to find molecules that modulate BIM splicing.
  • The efficacy of identified ASOs was tested in BIM deletion-containing cells for their ability to restore exon 4 splicing, apoptosis, and TKI sensitivity.

Main Results:

  • Eight out of 67 screened ASOs successfully corrected the aberrant BIM splicing in cells with the deletion polymorphism.
  • These ASOs significantly increased exon 4 splicing levels, restoring the pro-apoptotic BH3 domain.
  • The corrected splicing led to restored imatinib-induced apoptosis and resensitization of resistant CML cells to TKIs.

Conclusions:

  • Splice-switching BIM ASOs can effectively resensitize TKI-resistant CML cells caused by the BIM deletion polymorphism.
  • This study demonstrates the potential of ASOs as a precision medicine strategy to overcome drug resistance in CML.
  • Further optimization of these ASOs could lead to novel adjuvant therapies for BIM-polymorphism-associated TKI-resistant CML and other cancers.
Keywords:
BIMalternative splicingantisense oligonucleotideschronic myeloid leukemiaimatinib

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