A 62-year-old Indian man presents with fatigue, early satiety, and left upper quadrant pain. CBC shows WBC 185,000/μL with left-shifted granulocytes (myelocytes > metamyelocytes > bands > segmented), basophilia, and thrombocytosis. Bone marrow is hypercellular. The karyotype notation marked **D** in the diagram reads 46,XY,t(9;22)(q34;q11). Which of the following best describes the molecular consequence of the translocation event denoted by this karyotype notation?

Explanation

## Why "Production of a constitutively active BCR-ABL1 tyrosine kinase fusion protein driving uncontrolled myeloid proliferation" is right The karyotype notation **D** — 46,XY,t(9;22)(q34;q11) — denotes a reciprocal translocation between chromosome 9 (band q34, where ABL1 resides) and chromosome 22 (band q11, where BCR resides). This translocation produces the Philadelphia chromosome [derivative chromosome 22, der(22)], which contains the BCR-ABL1 fusion gene. The fusion protein is a constitutively active (unregulated) tyrosine kinase that phosphorylates multiple downstream targets (STAT5, PI3K, RAS), driving proliferation, inhibiting apoptosis, and causing the myeloproliferative phenotype seen in this patient (massive splenomegaly, left-shifted granulocytes, thrombocytosis, elevated WBC). This is pathognomonic for chronic myeloid leukemia (CML), present in ~95% of cases. [Harrison 21e Ch 102] ## Why each distractor is wrong - **Loss of the ABL1 tumor suppressor gene on chromosome 9, leading to unchecked cell division**: ABL1 is not a tumor suppressor; it is a proto-oncogene. The translocation does not delete ABL1 but rather relocates it to the BCR locus, creating a fusion oncogene. Loss of ABL1 alone would not cause CML. - **Amplification of the MYC oncogene on chromosome 22, resulting in increased transcription of growth-promoting genes**: MYC is located on chromosome 8, not chromosome 22. The t(9;22) translocation does not involve MYC amplification. This describes Burkitt lymphoma (t(8;14)), not CML. - **Deletion of the TP53 gene on chromosome 17, impairing apoptosis and cell cycle checkpoints**: TP53 mutations are not the primary driver of chronic-phase CML. TP53 loss is associated with blast crisis (transformation) and other malignancies, but the t(9;22) translocation itself does not directly delete TP53. The anchor is BCR-ABL1 fusion, not TP53 loss. **High-Yield:** The Philadelphia chromosome t(9;22)(q34;q11) creates BCR-ABL1 fusion oncogene — a constitutively active tyrosine kinase pathognomonic for CML (~95%) and Philadelphia-positive ALL; TKI therapy (imatinib, dasatinib, nilotinib) targets this fusion protein and has transformed CML from a fatal disease to one with near-normal life expectancy in optimal responders. [cite: Harrison 21e Ch 102]