A 54-year-old man presents to the clinic for a routine physical examination. He reports feeling generally well but mentions early satiety and a full sensation in his left upper abdomen over the past three months. He denies fever, night sweats, or bone pain. On physical examination, his spleen is palpable 6 cm below the left costal margin. There is no significant lymphadenopathy.
Laboratory studies show the following:
Hemoglobin: 11.2 g/dL
Platelet count: 480,000/μL
White blood cell count: 110,000/μL
Differential: 50% neutrophils, 15% myelocytes, 10% metamyelocytes, 5% bands, 4% basophils, 2% eosinophils, and 2% blasts.
Leukocyte alkaline phosphatase (LAP) score: Low
Which of the following cytogenetic abnormalities is the underlying cause of this patient's condition?
The correct answer is:
B) t(9;22) translocation involving BCR-ABL1
This patient is presenting with chronic myelogenous leukemia (CML). CML is a myeloproliferative neoplasm characterized by the dysregulated production of mature and maturing granulocytes (neutrophils, myelocytes, metamyelocytes, basophils). The hallmark of CML is the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9. The resulting BCR-ABL1 fusion protein is a constitutively active tyrosine kinase that drives uncontrolled cellular proliferation and inhibits apoptosis.
Key clinical and lab features include:
Massive Splenomegaly: Often presenting as early satiety.
Leukocytosis with left shift: A full spectrum of myeloid cells is seen on the smear, but unlike acute leukemia, the blast count is low (<10% in the chronic phase).
Basophilia: An increase in basophils is a highly characteristic finding in CML.
Low LAP Score: The leukocyte alkaline phosphatase score is low in CML because the malignant white cells are biochemically abnormal. This helps distinguish CML from a leukemoid reaction (an extreme response to infection), where the LAP score is high.
Answer choice A: t(8;14), is incorrect. This is associated with Burkitt lymphoma, leading to the overexpression of the c-myc oncogene. It typically presents with rapidly enlarging lymph nodes or an abdominal mass.
Answer choice C: t(11;14), is incorrect. This is the hallmark of mantle cell lymphoma, leading to the overexpression of cyclin D1, which promotes cell cycle progression.
Answer choice D: t(14;18), is incorrect. This is associated with follicular lymphoma, leading to the overexpression of Bcl-2, an anti-apoptotic protein.
Answer choice E: t(15;17), is incorrect. This is the translocation for acute promyelocytic leukemia (APL). While it involves the myeloid lineage, it presents acutely with disseminated intravascular coagulation (DIC) and numerous Auer rods, rather than the indolent, high-count left shift of CML.
Key Learning Point
Chronic myelogenous leukemia (CML) is defined by the t(9;22) Philadelphia chromosome, creating the BCR-ABL1tyrosine kinase. It presents with a high WBC count, a full spectrum of myeloid precursors, and basophilia. The first-line treatment is with tyrosine kinase inhibitors (TKIs) like imatinib, which specifically target the ATP-binding site of the BCR-ABL1 protein.
