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BCR-ABL 1

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).

Key Details

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).

4. Diagnostic Tests for BCR-ABL1 at Jaipur Molecular Lab

  • 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).

6. Treatment and Therapeutic Targeting:

  • The identification of BCR-ABL1 at Jaipur Molecular Lab has led to targeted therapies that revolutionized the treatment of CML and Ph-positive ALL:
    • 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.