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?

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 ### Cytogenetic Abnormalities in Chronic Leukemias | Leukemia | Hallmark Abnormality | Frequency | Other Abnormalities | |----------|----------------------|-----------|---------------------| | **CML** | t(9;22) BCR-ABL1 | >95% | Additional Ph chromosome, trisomy 8, isochromosome 17q | | **CLL** | del(13q) | 55% | Trisomy 12 (25%), del(11q) (20%), del(17p) (10%) | | **CNL** | None specific | — | RAS mutations, CSF3R mutations | | **CEL** | FIP1L1-PDGFRA | 80% | PDGFRB, FGFR1 rearrangements | **High-Yield:** 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.