A 53-year-old man comes to the physician due to frequent headaches and dizziness. He has a history of hypertension and peptic ulcer disease. His medications include daily chlorthalidone and antacids as needed. The patient's temperature is 37 C (98.6 F), blood pressure is 146/92 mm Hg, pulse is 89/min, and respirations are 16/min. His BMI is 26 kg/m². Physical examination shows facial plethora and moderate splenomegaly. Laboratory results are as follows: This patient most likely has a mutation in which of the following types of proteins?

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11ec160b_3992_b5ad_9249_a15487359d21_MD0001_00 This patient most likely has polycythemia vera, a myeloproliferative disorder characterized by uncontrolled erythrocyte production. Patients frequently present with nonspecific symptoms (eg, headache, weakness, diaphoresis), aquagenic pruritus, facial plethora (reddish complexion), and splenomegaly. Associated conditions include peptic ulcer disease (altered mucosal blood flow due to increased viscosity) and gouty arthritis (higher red cell turnover). Laboratory studies show increased erythrocyte mass, thrombocytosis, leukocytosis, and low erythropoietin levels. Erythrocyte indices are usually normal. Polycythemia vera is caused by abnormal transduction of erythropoietin growth signals. The erythropoietin receptor has no intrinsic kinase activity and must interact with Janus kinase 2 (JAK2), a cytoplasmic (non-receptor) tyrosine kinase, to initiate downstream signaling. Virtually all patients with polycythemia vera have a mutation in JAK2 that causes constitutive activation of its kinase domain, resulting in clonal proliferation of myeloid cells. JAK2 mutations have also been implicated in essential thrombocythemia, primary myelofibrosis, and other myeloproliferative disorders. (Choice B) Burkitt lymphoma is characterized by translocation of the c-myc oncogene on chromosome 8 to the Ig heavy chain region on chromosome 14. This results in constitutive expression of c-Myc, a growth-stimulating transcription factor. (Choice C) Intrinsic receptor tyrosine kinases are receptors with intrinsic kinase activity that autophosphorylate and induce a downstream signaling cascade upon ligand binding. Examples include the receptors for insulin, insulin-like growth factor, and epidermal growth factor. Mutations causing excessive epidermal growth factor receptor activity occur in many solid tumors. (Choice D) Mutations of the p53 tumor suppressor are associated with Li-Fraumeni syndrome, an autosomal dominant disorder with predisposition to a variety of cancers, particularly sarcomas and tumors of the breast, brain, and adrenal cortex. (Choice E) Expression of vascular endothelial growth factor (VEGF) is required for tumor angiogenesis, a critical step in the process of tumor growth and metastasis. VEGF upregulation occurs in the vast majority of cancers. Educational objective: Polycythemia vera is a myeloproliferative disorder characterized by uncontrolled erythrocyte production. Virtually all patients with polycythemia vera have a mutation in JAK2, a non-receptor (cytoplasmic) tyrosine kinase associated with the erythropoietin receptor. __________ References: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. (http://www.ncbi.nlm.nih.gov/pubmed/17267906)

A 53-Year-Old Man Comes to the Physician Due to Frequent