USMLE PRACTICE QUESTION #127
TOPIC: Cell Signaling Pathways
USMLE practice question #127 will test your understanding of a commonly tested cell signaling pathways.
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A 62-year-old woman presents to the clinic with progressive fatigue, night sweats, and early satiety. Physical examination reveals splenomegaly. Laboratory studies demonstrate elevated leukocyte and platelet counts with reduced hemoglobin. Peripheral blood smear shows tear-drop-shaped red blood cells and immature myeloid precursors. A bone marrow biopsy confirms a hypercellular marrow with fibrosis. Genetic testing reveals a mutation in the JAK2 gene. Which of the following best describes the molecular mechanism by which this mutation contributes to her condition?
A) Constitutive activation of STAT transcription factors
B) Impaired dephosphorylation of receptor tyrosine kinases
C) Enhanced proteolysis of suppressor of cytokine signaling proteins
D) Loss of receptor affinity for negative regulatory proteins
E) Increased intracellular calcium release
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best describes the molecular mechanism by which this mutation contributes to her condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 1st order. 1st: Identify the consequences of the given mutation.
Step 3: Read the vignette carefully and ask yourself: “Based on the JAK2 gene mutation, the molecular mechanism contributing to her condition is _____________________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 62-year-old woman presents with progressive fatigue, night sweats, early satiety, and splenomegaly, along with laboratory findings of elevated leukocyte and platelet counts, reduced hemoglobin, and a peripheral blood smear showing tear-drop-shaped red blood cells and immature myeloid precursors. A bone marrow biopsy reveals hypercellular marrow with fibrosis, and genetic testing identifies a JAK2 mutation. These findings are diagnostic of a myeloproliferative neoplasm, most likely primary myelofibrosis.
ANSWER CHOICES:
CHOICE A: Constitutive activation of STAT transcription factors
Explanation: The JAK2 V617F mutation disrupts the autoinhibitory function of the pseudokinase domain on the kinase domain, leading to constitutive activation of JAK2. This results in continuous phosphorylation and activation of downstream STAT transcription factors, even in the absence of cytokine binding.
CHOICE B: Impaired dephosphorylation of receptor tyrosine kinases
Explanation: Impaired dephosphorylation can lead to prolonged receptor activation and downstream signaling through pathways like MAPK. However, this mechanism is not directly related to JAK2 mutations.
CHOICE C: Enhanced proteolysis of suppressor of cytokine signaling proteins
Explanation: Suppressor of cytokine signaling proteins are negative regulators of cytokine signaling that inhibit JAK-STAT activity. Their degradation could theoretically prolong JAK activity.
CHOICE D: Loss of receptor affinity for negative regulatory proteins
Explanation: Loss of receptor affinity for regulatory proteins does not explain the pathogenesis of MPNs. This affects TGF-beta pathways, which are involved in fibrosis, but not directly linked to JAK2 mutations.
CHOICE E: Increased intracellular calcium release
Explanation: Nuclear factor of activated T cells (NFAT) is activated by calcium signaling and plays a role in immune cell activation, but is unrelated to the pathogenesis of myeloproliferative neoplasms or JAK2 mutations.
FINAL VERDICT…
CORRECT ANSWER: A) Constitutive activation of STAT transcription factors
The JAK2 V617F mutation leads to constitutive activation of the JAK-STAT pathway by disrupting autoinhibition within the JAK2 protein. This results in persistent STAT phosphorylation and transcriptional activation of genes promoting myeloid cell proliferation and survival, driving the clinical manifestations seen in myeloproliferative neoplasms such as primary myelofibrosis.
KEY CONCEPTS:
JAK2 Mutation Pathophysiology:
The JAK2 V617F mutation substitutes valine with phenylalanine at codon 617 in the pseudokinase domain (JH2), disrupting its autoinhibitory function.
This leads to constitutive activation of JAK2 kinase activity and downstream STAT transcription factors, independent of cytokine binding.
Role of STAT Activation:
Activated STAT proteins regulate genes involved in hematopoietic cell proliferation, differentiation, and survival.
Constitutive STAT activation drives excessive production of red blood cells, platelets, or granulocytes depending on the specific MPN subtype (e.g., polycythemia vera, essential thrombocythemia, or primary myelofibrosis).
Clinical Features of Primary Myelofibrosis (PMF):
Symptoms include fatigue, night sweats, weight loss, early satiety (due to splenomegaly), and anemia.
Peripheral smear shows tear-drop-shaped red blood cells (dacrocytes) and immature myeloid precursors.
Bone marrow biopsy reveals fibrosis with hypercellularity.
Diagnostic Role of JAK2 Mutation Testing:
The JAK2 V617F mutation is present in ~95% of polycythemia vera cases and ~50–60% of essential thrombocythemia and primary myelofibrosis cases.
It is a key diagnostic marker for Philadelphia chromosome-negative myeloproliferative neoplasms.
Therapeutic Implications:
Targeted therapies like ruxolitinib (a JAK1/2 inhibitor) are used to manage symptoms and reduce spleen size in patients with MPNs.
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