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The silent players: Atypical BCR‑ABL isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)

  • Authors:
    • Xin Zhou
    • Ai Li
    • Dexiao Kong
    • Yuqi Shi
    • Peipei Zhang
    • Ningning Shan
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
    Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 162
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    Published online on: September 24, 2025
       https://doi.org/10.3892/or.2025.8995
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Abstract

Chronic myeloid leukemia (CML) is a hematological malignancy driven by diverse genetic aberrations, with the Philadelphia chromosome and its resultant BCR‑ABL1 fusion gene constituting key pathogenic drivers. Atypical BCR‑ABL1 fusion transcripts have distinctive structural and functional properties. Structural divergence in these variants leads to functional alterations of encoded oncoproteins, potentially influencing disease progression and therapeutic responsiveness. Conventional diagnostic modalities, including reverse transcription‑PCR and fluorescence in situ hybridization, may fail to detect rare variants, necessitating complementary high‑sensitivity techniques such as next‑generation sequencing). Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, remain cornerstone treatments; however, marked inter‑variant heterogeneity in TKI responsiveness is observed: Patients harboring e13a3/e14a3 transcripts generally show favorable prognoses, while those with e1a3/e6a2 variants demonstrate an increased risk of relapse and/or TKI resistance, often requiring multimodal strategies combining chemotherapy or allogeneic hematopoietic stem cell transplantation. Although Chimeric Antigen Receptor)‑T cell therapy has shown promise in treating (Philadelphia chromosome‑positive B‑cell Acute Lymphoblastic Leukemia, its application in CML, particularly in variants such as e1a3 or e6a2, is not currently recommended as a first‑line treatment. Despite advances in elucidating the clinical implications of fusion gene heterogeneity in leukemogenesis, the prognostic value of atypical BCR‑ABL1 isoforms requires further validation through multicenter studies with extended cohorts. This review aimed to summarize cases of atypical fusion genes in CML, with analysis of clinical characteristics, therapeutic interventions, and prognostic outcomes, to provide clinicians with enhanced reference material for improved patient management.
View Figures

Figure 1

Clinical roadmap for atypical
BCR-ABL1 testing. BCR, breakpoint cluster region; ABL1,
abelson leukemia1; RT-q, reverse transcription-quantitative; NGS,
next-generation sequencing; CML, chronic myeloid leukemia; TKI,
tyrosine kinase inhibitor; seq, sequencing; dd, digital droplet;
MRD, minimal residual disease; MR, molecular response; HSCT,
hematopoietic stem cell transplantation.

Figure 2

Schematic diagram of common and rare
transcripts. Colors differentiate gene exons (with ABL1 in blue and
BCR in red), arrows to indicate the direction of the gene, and
dashed lines to represent mRNA splicing connections. Each mRNA
splicing variant is composed of specific exon combinations, and a
scale bar indicates the gene length. BCR, breakpoint cluster
region; ABL1, abelson leukemia 1.

Figure 3

Atypical BCR-ABL1 variants and
their clinical significance. BCR-breakpoint cluster region; ABL1,
abelson leukemia 1; RT, reverse transcription; FISH, fluorescence
in situ hybridization; gen, generation; NGS, next-generation
sequencing; TKI, tyrosine kinase inhibitor; RALGPS, Ral GEF with PH
domain and SH3 binding motif.

Figure 4

PRISMA flow diagram. CML, chronic
myeloid leukemia; Ph, philadelphia chromosome; ALL, acute
lymphoblastic leukemia.
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Spandidos Publications style
Zhou X, Li A, Kong D, Shi Y, Zhang P and Shan N: The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review). Oncol Rep 54: 162, 2025.
APA
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., & Shan, N. (2025). The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review). Oncology Reports, 54, 162. https://doi.org/10.3892/or.2025.8995
MLA
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., Shan, N."The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)". Oncology Reports 54.6 (2025): 162.
Chicago
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., Shan, N."The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)". Oncology Reports 54, no. 6 (2025): 162. https://doi.org/10.3892/or.2025.8995
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Spandidos Publications style
Zhou X, Li A, Kong D, Shi Y, Zhang P and Shan N: The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review). Oncol Rep 54: 162, 2025.
APA
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., & Shan, N. (2025). The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review). Oncology Reports, 54, 162. https://doi.org/10.3892/or.2025.8995
MLA
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., Shan, N."The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)". Oncology Reports 54.6 (2025): 162.
Chicago
Zhou, X., Li, A., Kong, D., Shi, Y., Zhang, P., Shan, N."The silent players: Atypical <em>BCR‑ABL </em>isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review)". Oncology Reports 54, no. 6 (2025): 162. https://doi.org/10.3892/or.2025.8995
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