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Updated: Jun 18, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary
Daniel Nowak1, Seishi Ogawa, Markus Müschen
1Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, CA 90048, USA. Daniel.nowak@medma.uni-heidelberg.de
Abstract:
To elucidate whether tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI-resistant chronic myeloid leukemia patients with 250K single nucleotide polymorphism arrays. From 20 patients, matched serial samples of pretreatment and TKI resistance time points were available. Eleven of the 45 TKI-resistant patients had mutations of BCR-ABL1, including 2 T315I mutations. Besides known TKI resistance-associated genomic lesions, such as duplication of the BCR-ABL1 gene (n = 8) and trisomy 8 (n = 3), recurrent submicroscopic alterations, including acquired uniparental disomy, were detectable on chromosomes 1, 8, 9, 17, 19, and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in 3 patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI-induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity.
Insights
Genomic alterations, including BCR-ABL1 mutations and chromosomal changes, are linked to tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). These changes may drive disease progression and TKI evasion.
Area of Science:
- Oncology
- Genetics
- Hematology
Background:
- Chronic myeloid leukemia (CML) is often treated with tyrosine kinase inhibitors (TKIs).
- Resistance to TKIs remains a significant challenge in CML management.
- Understanding the genomic landscape of TKI resistance is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the association between genomic alterations and TKI resistance in CML.
- To identify novel genetic markers predictive of TKI resistance.
Main Methods:
- Analysis of DNA samples from 45 TKI-resistant CML patients using 250K single nucleotide polymorphism arrays.
- Comparison of pretreatment and TKI-resistant samples from 20 patients.
- Detection of gene mutations, copy number variations, and other submicroscopic alterations.
Main Results:
- BCR-ABL1 mutations, including T315I, were found in 11 patients.
- Known resistance-associated alterations like BCR-ABL1 duplication and trisomy 8 were observed.
- Recurrent submicroscopic alterations, including acquired uniparental disomy, were detected on multiple chromosomes.
- Newly acquired deletions of the IGLC1 locus on chromosome 22 were identified in patients with blast crisis.
Conclusions:
- Genomic alterations play a key role in the development of TKI resistance in CML.
- TKI-induced selection may favor subclones with specific genomic changes, leading to disease progression.
- These findings may inform the development of targeted therapies and resistance monitoring strategies.
