A 52-year-old man presents with fatigue and abdominal fullness. Routine CBC shows WBC 180,000/µL with full spectrum of myeloid maturation including increased basophils. Karyotype analysis reveals the shortened chromosome 22 marked as **A** in the diagram. Which of the following best explains the pathogenic mechanism underlying this patient's disease?

Explanation

## Why "Reciprocal translocation t(9;22) resulting in BCR-ABL1 fusion gene producing constitutively active tyrosine kinase" is right The shortened chromosome 22 marked **A** is the Philadelphia chromosome, the pathognomonic cytogenetic hallmark of chronic myeloid leukemia (CML). This chromosome results from a reciprocal translocation t(9;22)(q34;q11) in which the ABL1 proto-oncogene from chromosome 9q34 is translocated to the breakpoint cluster region (BCR) on chromosome 22q11. This creates the BCR-ABL1 fusion gene on the shortened chromosome 22, which produces a constitutively active tyrosine kinase (p210 in CML). This aberrant kinase drives unregulated myeloid proliferation, explaining the massive leukocytosis and full spectrum of myeloid maturation seen in this patient. This is the first cancer-associated chromosomal abnormality ever discovered (Nowell & Hungerford, 1960) and is present in >95% of CML cases (Harrison Principles of Internal Medicine 21e Ch 109). ## Why each distractor is wrong - **Deletion of the long arm of chromosome 22 leading to loss of tumor suppressor genes**: This describes a loss-of-function mechanism (like in neurofibromatosis type 2 or other tumor suppressor syndromes), not the gain-of-function mechanism of BCR-ABL1. The Philadelphia chromosome is not a deletion but a translocation that creates a novel fusion gene. - **Insertion of ABL1 proto-oncogene into the centromeric region of chromosome 22**: While ABL1 does move to chromosome 22, it specifically inserts into the BCR locus at 22q11, not the centromeric region. The precise breakpoint location is critical to the pathogenesis and diagnosis of CML. - **Amplification of the MYC oncogene on chromosome 22 driving unregulated cell proliferation**: MYC is located on chromosome 8, not chromosome 22. MYC amplification is associated with Burkitt lymphoma and other hematologic malignancies, not CML. The oncogenic driver in CML is BCR-ABL1, not MYC. **High-Yield:** Philadelphia chromosome t(9;22) = BCR-ABL1 fusion = CML pathognomonic hallmark; constitutively active tyrosine kinase drives unregulated myeloid proliferation; TKI therapy (imatinib, dasatinib, nilotinib) targets this kinase. [cite: Harrison Principles of Internal Medicine 21e Ch 109; Wintrobe's Clinical Hematology 14e]