A 64-year-old man comes to the office due to several weeks of worsening back pain, fatigue, and polyuria. Physical examination reveals mucosal pallor and diffuse bony tenderness. Laboratory studies are significant for normocytic anemia, hypercalcemia, and renal failure. Serum protein electrophoresis demonstrates a monoclonal spike in the gamma globulin region. Bone marrow biopsy shows a large number of abnormal plasma cells. Treatment with lenalidomide is started; this medication increases affinity of E3 ubiquitin ligase enzyme to substrate transcription factors. Which of the following is the most likely effect of this medication on these transcription factors?
Multiple myeloma is a plasma cell neoplasm associated with the overproduction of monoclonal immunoglobulins. Proliferation of neoplastic plasma cells in the bone marrow often causes bone pain (eg, back pain), hypercalcemia (eg, polyuria), and osteolytic lesions; patients also frequently develop normocytic anemia and renal insufficiency. Treatment frequently includes medications that inhibit proteasome activity (eg, bortezomib) or increase ubiquitination of regulatory proteins produced in excess in neoplastic cells (eg, lenalidomide).
Lenalidomide is a derivative of thalidomide, an antiemetic agent used in pregnancy until significant teratogenic effects were identified. Lenalidomide increases the binding affinity of the E3 ubiquitin ligase complex to specific transcription factors (TFs) (eg, Ikaros and Aiolos 2 zinc finger transcription factors) that are overexpressed in myeloma cells. Binding attaches ubiquitin to the TFs, which leads to their subsequent destruction by the proteasome. Because these TFs are required for myeloma cell survival, diminished intracellular concentrations cause cell death. Other mature B-cell malignancies such as mantle cell lymphoma and myelodysplastic syndrome (some cases are caused by B-cell proliferation) also overexpress these TFs; therefore, lenalidomide is often effective against these neoplasms.
(Choice A) TFs are proteins that bind to a specific DNA sequence to increase or suppress its transcription to messenger RNA; they are not expressed on the cell surface.
(Choice B) Lysosomes are membrane-bound organelles with hydrolytic enzymes that break down molecules from outside the cell (via endocytosis) or within the cytoplasm (autophagy). Although lysosomes and proteasomes are the 2 major pathways of protein degradation in the cell, lysosomes digest proteins independent of ubiquitination; therefore, lenalidomide does not alter lysosome proteolysis.
(Choice C) Ubiquitin binding does not alter the way TFs interact with DNA; instead, it results in increased proteolysis of the TFs by proteasomes. In contrast, phosphorylation or acetylation can affect TF binding to promoter regions of DNA.
(Choice E) Proteins targeted for the nucleus have nuclear localization signals, short chains of amino acids that promote transport into the nucleus. These are added during protein synthesis in the endoplasmic reticulum; ubiquitination does not affect nuclear localization.
Educational objective:
Multiple myeloma is often treated with medications that block proteasome activity (eg, bortezomib) or increase ubiquitination of specific transcription factors (eg, lenalidomide). Lenalidomide increases E3 ubiquitin ligase binding to transcription factors overexpressed in myeloma, which results in increased transcription factor destruction by the proteosome and subsequent cancer cell death.