A 67-year-old woman comes to the office due to progressive fatigue and anorexia over the last 6 months. She has lost 4 kg (8.8 lb), which she attributes to early satiety. She has had no abdominal pain, night sweats, or fevers. The patient's past medical history is significant for hypothyroidism, hypertension, and gout. She does not use tobacco, alcohol, or illicit drugs and is compliant with her medications. Temperature is 37.3 C (99.2 F), blood pressure is 128/82 mm Hg, and pulse is 88/min. The patient is slightly thin but well nourished. Mild mucosal pallor is present. There is no lymphadenopathy in the cervical or supraclavicular chains. Cardiopulmonary examination is normal. A spleen tip is palpable with deep exhalation. Laboratory results are as follows: Florescence in situ hybridization reveals an abnormality in chromosome 22. Which of the following is the most important target in treating this patient's disease?

Question

A 67-year-old woman comes to the office due to progressive fatigue and anorexia over the last 6 months.  She has lost 4 kg (8.8 lb), which she attributes to early satiety.  She has had no abdominal pain, night sweats, or fevers.  The patient's past medical history is significant for hypothyroidism, hypertension, and gout.  She does not use tobacco, alcohol, or illicit drugs and is compliant with her medications.  Temperature is 37.3 C (99.2 F), blood pressure is 128/82 mm Hg, and pulse is 88/min.  The patient is slightly thin but well nourished.  Mild mucosal pallor is present.  There is no lymphadenopathy in the cervical or supraclavicular chains.  Cardiopulmonary examination is normal.  A spleen tip is palpable with deep exhalation.  Laboratory results are as follows:  Florescence in situ hybridization reveals an abnormality in chromosome 22.  Which of the following is the most important target in treating this patient's disease?

Quizplus · Accepted Answer

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder driven by the abnormal fusion gene BCR-ABL (due to a translocation between chromosomes 9 and 22). This gene causes leukemogenesis due to a constitutively active tyrosine kinase. First-line treatment for most CML patients involves tyrosine kinase inhibitors such as imatinib. Although these drugs are not curative, they often can induce long-term remission. BCR-ABL Patients with CML may present asymptomatically, although fatigue, night sweats, weight loss, and abdominal fullness (due to splenomegaly) are not uncommon. Patients may experience weight loss and early satiety from splenomegaly. Peripheral blood smear in CML reveals dramatic leukocytosis (often >100,000/mm³) with absolute basophilia and a shift toward very early neutrophil precursors (promyelocytes, myelocytes). Peripheral blood smear (Choice A) DNA methylation mutations are found in many hematologic malignancies including acute myelogenous leukemia and certain myelodysplastic syndromes. Drugs are available to counter the effects of these mutations, but they are not currently used in CML. (Choices B and D) Methotrexate alters folic acid metabolism and reduces the ability of the body to generate thymidine as folate is an important component of thymidine synthesis. Methotrexate is used in many autoimmune conditions and neoplasms but is not used in the treatment of CML. (Choice C) The retinoic acid receptor is involved in the pathogenesis of acute promyelocytic leukemia (APML), a subtype of acute myeloid leukemia. All-trans retinoic acid is a crucial component of therapy for APML, which often presents with complications due to pancytopenia. Educational objective: Chronic myeloid leukemia (CML) is driven by a reciprocal translocation of chromosomes 9 and 22 forming the BCR-ABL fusion gene. This gene creates a constitutively active tyrosine kinase. Tyrosine kinase inhibitors such as imatinib are a key therapy in the treatment of CML.

A 67-Year-Old Woman Comes to the Office Due to Progressive