A 67-year-old man is evaluated for persistent lower back pain and fatigue. The patient has no other medical conditions and takes no medications. Laboratory testing shows anemia and renal dysfunction. Serum total protein levels are elevated, and electrophoresis of the serum proteins reveals a narrow spike in the gamma globulin region. A subsequent bone marrow biopsy shows abnormal marrow cells. A medication that blocks cellular proteasome action is administered. This treatment is most likely to cause which of the following effects on the abnormal cells?

Question

A 67-year-old man is evaluated for persistent lower back pain and fatigue.  The patient has no other medical conditions and takes no medications.  Laboratory testing shows anemia and renal dysfunction.  Serum total protein levels are elevated, and electrophoresis of the serum proteins reveals a narrow spike in the gamma globulin region.  A subsequent bone marrow biopsy shows abnormal marrow cells.  A medication that blocks cellular proteasome action is administered.  This treatment is most likely to cause which of the following effects on the abnormal cells?

Quizplus · Accepted Answer

11ec160b_3be5_a5f1_9249_e3db7c3c99a2_MD0001_00 This patient's manifestations (anemia, back pain, renal insufficiency), monoclonal protein spike on electrophoresis, and bone marrow findings indicate likely multiple myeloma (MM), a plasma cell malignancy associated with the overproduction of monoclonal immunoglobulins or IgG fragments (eg, IgG light chains). Treatment regimens for MM often incorporate medications that block proteasome function (eg, bortezomib). The proteasome is a barrel-shaped structure with a proteolytic core that degrades ubiquitin-tagged proteins. Proteasome inhibition results in the accumulation of damaged and misfolded proteins that have a cytotoxic effect. MM cells are particularly susceptible to proteasome inhibition because they generate extremely high quantities of secretory proteins (eg, monoclonal immunoglobulins), some of which misfold and aggregate within the endoplasmic reticulum. Increased stress on the endoplasmic reticulum triggers an unfolded protein response that eventually leads to activation of caspases and cellular apoptosis. (Choice A) Cytotoxic T-cell destruction of cancer cells is augmented by checkpoint inhibitor immunotherapies such as those that target the programmed cell death 1 receptor and CTLA-4. These drugs are often used in the treatment of MM but augmented cytotoxic T-cell function is not related to proteosome inhibition. (Choice B) Azacitidine is a cytidine analogue that inhibits DNA methyltransferase. It reduces DNA methylation and alters gene expression, leading to reduced protein synthesis and increased cellular differentiation. It is toxic to abnormal hematopoietic cells but is used primarily to treat myelodysplastic syndrome. (Choice C) RNA splicing is done by the nuclear spliceosome, which removes introns from transcribed pre-mRNA. The proteasome does not affect RNA splicing. (Choice D) All-trans-retinoic acid is used in the treatment of acute promyelocytic leukemia. It works by promoting differentiation of neoplastic cells into mature neutrophils. Educational objective: Multiple myeloma, a plasma cell malignancy associated with significant production of secretory proteins (eg, monoclonal immunoglobulins), is frequently treated with proteasome inhibitors (eg, bortezomib). These drugs block the degradation of ubiquitinated proteins by the proteosome, which leads to accumulation of abnormally folded proteins that trigger cellular apoptosis. __________ References: Proteasome inhibitors: structure and function. (http://www.ncbi.nlm.nih.gov/pubmed/29935898) Proteasome inhibitors in multiple myeloma: 10 years later. (http://www.ncbi.nlm.nih.gov/pubmed/22645181)

A 67-Year-Old Man Is Evaluated for Persistent Lower Back Pain