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BCR-ABL1 Testing

BCR-ABL1 is a fusion gene that arises from the rearrangement of two separate genes: BCR (breakpoint cluster region) and ABL1 (Abelson proto-oncogene 1). This rearrangement occurs due to a chromosomal translocation, specifically t(9;22)(q34;q11), which produces the Philadelphia chromosome (Ph).

About BCR-ABL1

1. Structure of BCR-ABL1:

  • BCR gene: Located on chromosome 22, it instructs the production of a protein involved in signal transduction and cell growth regulation.
  • ABL1 gene: Found on chromosome 9, it encodes a tyrosine kinase that regulates the cell cycle, differentiation, and apoptosis.
  • The fusion of these genes creates a hybrid oncogene, BCR-ABL1, which produces a constitutively active tyrosine kinase.

2. Mechanism of Action:

  • The BCR-ABL1 protein functions as a continuously active tyrosine kinase.
  • This activity results in:
    • Unregulated cell proliferation.
    • Reduced apoptosis (cell death).
    • Increased genetic instability.
  • It disrupts normal cellular signaling pathways, making it a key driver of leukemogenesis (the development of leukemia).

See Image:

An illustration showing the formation of the BCR-ABL1 fusion gene. The image starts with normal chromosomes 9 and 22. A chromosomal break occurs, leading to a translocation where part of chromosome 9 (ABL1 gene) and part of chromosome 22 (BCR gene) fuse. The resulting Philadelphia chromosome (changed chromosome 22) contains the BCR-ABL1 fusion gene, depicted as a hybrid of the two original segments. And BCR-ABL1 diagnosed at Jaipur Molecular Lab.

3. Clinical Relevance:

  • Diseases Associated with BCR-ABL1:
    • Chronic Myeloid Leukemia (CML): Present in over 95% of CML cases.
    • Acute Lymphoblastic Leukemia (ALL): Detected in approximately 25% of adult ALL cases and 2-4% of pediatric ALL cases.
    • Rarely identified in acute myeloid leukemia (AML).

Testing Methods

  • Cytogenetics (Karyotyping): Detects the Philadelphia chromosome.
  • Fluorescence In Situ Hybridization (FISH): Visualizes the fusion of BCR and ABL1 at the chromosomal level.
  • Quantitative PCR (qPCR): Measures BCR-ABL1 transcript levels, which is essential for diagnosing and monitoring treatment response.
  • Next-Generation Sequencing (NGS): Identifies BCR-ABL1 presence and any mutations in the fusion gene.

5. Types of BCR-ABL1 Transcripts:

  • The fusion gene generates different transcripts based on the breakpoints in the BCR and ABL1 genes:
    • p190 (e1a2): Commonly found in ALL.
    • p210 (b2a2 or b3a2): Most frequently associated with CML.
    • p230: Rare, linked to chronic neutrophilic leukemia (CNL).

Clinical Use

  • BCR-ABL1 results can support diagnosis, treatment selection, and response monitoring when interpreted by the treating clinician.
    • Tyrosine Kinase Inhibitors (TKIs):
      • Imatinib (Gleevec): A first-generation TKI that specifically inhibits BCR-ABL1 kinase.
      • Dasatinib, Nilotinib: Second-generation TKIs for patients resistant or intolerant to imatinib.
      • Ponatinib: A third-generation TKI designed for BCR-ABL1 mutations, including the T315I mutation.
    • Allogeneic Stem Cell Transplant: An option for advanced or TKI-resistant cases.
    • qPCR Monitoring: Used to assess minimal residual disease (MRD).

Prognostic Implications:

  • Good Prognosis: CML patients treated with TKIs often achieve long-term remission.
  • Resistance: Mutations in the BCR-ABL1 kinase domain, such as T315I, may cause resistance, requiring alternative treatments like ponatinib.

This information is for general education and does not replace medical advice. Test selection and interpretation should be discussed with a qualified clinician.