Resistance to imatinib in patients with chronic myelogenous leukemia and the splice variant BCR-ABL1(35INS)
Open accessAbstract
Purpose In patients with chronic myelogenous leukemia (CML), point mutations in the BCR-ABL1 kinase domain are the most common cause of treatment failure with a tyrosine kinase inhibitor (TKI). It is not clear whether the splice variant BCR-ABL1(35INS) is also associated with treatment failure.Patients and methods We reviewed all CML patients who had BCR-ABL1 kinase mutation analysis performed between August 1, 2007, and January 15, 2014. Patients who had BCR-ABL1(35INS) detected had their medical records reviewed to determine response to TKI therapy.Results Two hundred and eighty four patients had kinase mutation testing performed; of these, 64 patients (23%) had BCR-ABL1(35INS) detected. Forty-five patients were in chronic phase (70%), 10 were in accelerated phase (16%), 6 were in blastic phase (9%), and 3 were in other settings (5%). Of the 34 chronic phase patients who began therapy with imatinib, 23 patients (68%) failed therapy: 8 patients (24%) had primary refractory disease, 11 patients (32%) progressed, and 4 patients (12%) had disease progression after dose interruption. In contrast to the patients with disease progression or lack of response, none of 23 patients who were responding to imatinib had BCR-ABL1(35INS) detected. DNA sequencing of commonly mutated spliceosomal genes SF3B1, U2AF1, SRSF2, ZRSR2, SFA31, PRPF408, U2A565, and SF1 did not reveal mutations in seven BCR-ABL1(35INS) -positive patients tested.Conclusions The splice variant BCR-ABL1(35INS) is frequently found in patients who are resistant to imatinib. Mutations in the commonly mutated spliceosomal proteins do not contribute to this association.
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Previous studies showed that aberrant RNA splicing in BCR-ABL variants (BCR-ABL35INS) has been associated with poor response to TKI treatment (Imatinib).
“Previous studies showed that aberrant RNA splicing in BCR-ABL variants (BCR-ABL35INS) has been associated with poor response to TKI treatment (Imatinib) [86–88].”
From GOLDEN fusion: a graph-oriented learning with domain-embedding network fusion for generating super gene sets in functional genomics (2026) · cites this paper as [87]
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- Authors
- Berman, E., Jhanwar, S., Hedvat, C., Arcila, M. E., Wahab, O. A., Levine, R., Maloy, M., Ma, W., & Albitar, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- NYU Langone Health (US)
- NeoGenomics (United States) (US)
- Corresponding author
- Berman, Ellin
- Venue
- Leukemia Research
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 49
- Pages
- 108-112
- ISSN
- 0145-2126 (ISSN-L)
- PMC
- PMC5625826
- OpenAlex
- W2513330489
- Cited by
- 41
- References
- 32
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 1
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Leukemia Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- chronic myeloid leukemia, BCR-ABL1, imatinib resistance, tyrosine kinase inhibitors, kinase domain mutations, SF3B1, U2AF1, SRSF2, ZRSR2, treatment failure, disease progression
- MeSH terms
- Imatinib Mesylate, Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, RNA Splicing, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutagenesis, Insertional, Treatment Failure, Sequence Analysis, DNA, Protein Kinase Inhibitors, Young Adult
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