A 53-year-old man comes to the clinic due to frequent headaches and dizziness. The patient has a history of hypertension and peptic ulcer disease. His medications include daily chlorthalidone and antacids as needed. Temperature is 37 C (98.6 F), blood pressure is 146/92 mm Hg, pulse is 89/min, and respirations are 16/min. BMI is 26 kg/m2. Physical examination shows facial plethora and moderate splenomegaly. Laboratory results are as follows:
| Complete blood count | |
| Hemoglobin | 21.5 g/dL |
| Hematocrit | 64% |
| Erythrocytes | 7.6 million/mm3 |
| Mean corpuscular volume | 90 μm3 |
| Mean corpuscular hemoglobin | 31 pg/cell |
| Mean corpuscular hemoglobin concentration | 33% Hb/cell |
| Red blood cell distribution width | 14.0% (n = 10.3%-14.1%) |
| Platelets | 545,000/mm3 |
| Leukocytes | 15,500/mm3 |
This patient most likely has a mutation affecting which of the following types of protein?
Show Explanatory Sources
This patient's striking elevation in hemoglobin concentration (> 18.5 g/dL) is most likely due to polycythemia vera, a myeloproliferative disorder characterized by uncontrolled erythrocyte production. Patients frequently experience nonspecific symptoms (eg, headache, dizziness); more specific symptoms include aquagenic pruritus and facial plethora/splenomegaly (vascular congestion). Complications include peptic ulcer disease (altered mucosal blood flow due to increased viscosity) and gouty arthritis (higher erythrocyte turnover). Laboratory studies show increased erythrocyte mass and low erythropoietin levels; thrombocytosis and leukocytosis are also characteristic of polycythemia vera. 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 non-receptor tyrosine kinase found in the cytoplasm, to initiate downstream signaling. Almost all patients with polycythemia vera have a mutation in JAK2 that causes constitutive activation of the protein's 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 A) Burkitt lymphoma is characterized by translocation of the Myc oncogene on chromosome 8 to the Ig heavy chain region on chromosome 14. This translocation results in constitutive expression of Myc, a growth-stimulating transcription factor.
(Choice C) Receptor tyrosine kinases are transmembrane 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 in the p53 tumor suppressor are associated with Li-Fraumeni syndrome, an autosomal dominant disorder that predisposes to various 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 during tumor growth and metastasis. VEGF upregulation occurs in most cancers.
Educational objective:
Polycythemia vera is a myeloproliferative disorder characterized by uncontrolled erythrocyte production. Almost all patients with polycythemia vera have a mutation in the JAK2 gene, which encodes a non-receptor (cytoplasmic) tyrosine kinase associated with the erythropoietin receptor.