In a study of 500 patients with chronic leukemias diagnosed over 5 years at a tertiary center in Delhi, the distribution was: CML 210 cases, CLL 180 cases, CNL 45 cases, and other chronic leukemias 65 cases. What is the most common cytogenetic abnormality found in the CML cohort?
A. del(13q)
B. t(9;22) Philadelphia chromosome
C. t(11;14)
D. Trisomy 12
Explanation
Philadelphia Chromosome in CML
Key Point
The t(9;22) Philadelphia chromosome is present in >95% of CML cases and is the defining cytogenetic abnormality of CML. It results in the BCR-ABL1 fusion gene, which encodes a constitutively active tyrosine kinase.
Molecular Basis of t(9;22)
1.
Translocation mechanism: Reciprocal translocation between chromosome 9 (ABL locus) and chromosome 22 (BCR locus)
2.
Fusion protein: BCR-ABL1 tyrosine kinase (molecular weight ~210 kDa in most cases)
3.
Functional consequence: Loss of normal ABL regulation → uncontrolled myeloid proliferation
4.
Detection methods:
Conventional cytogenetics (G-banding)
Fluorescence in situ hybridization (FISH)
Reverse transcriptase PCR (RT-PCR) for BCR-ABL1 transcript
The Philadelphia chromosome is so characteristic of CML that its absence should prompt consideration of atypical CML or other myeloproliferative neoplasms. BCR-ABL1 positivity is the gold standard for CML diagnosis and is a prerequisite for TKI therapy.
Clinical Pearl
Patients with t(9;22)-positive CML who develop resistance to first-generation TKIs (imatinib) often harbor point mutations in the ABL kinase domain. Second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib) are used to overcome resistance.
Mnemonic: Ph = Philadelphia = 9;22 — the chromosome numbers are easy to recall as they sum to 31, and the translocation is named after the city where it was discovered.
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