A 70-year-old man develops progressive fatigue and easy bruising. He has had unintentional weight loss and episodic fevers. Physical examination shows splenomegaly and enlarged lymph nodes in the cervical, axillary, and inguinal regions. Complete blood count reveals anemia, thrombocytopenia, and leukocytosis. Peripheral blood smear shows an increased number of small, mature-appearing, abnormal lymphocytes, which express CD20 and kappa light chains. During treatment, the patient receives an agent that directly binds and inhibits BCL-2 protein. Which of the following is the most likely effect of this therapy on the abnormal cells?

Question

A 70-year-old man develops progressive fatigue and easy bruising.  He has had unintentional weight loss and episodic fevers.  Physical examination shows splenomegaly and enlarged lymph nodes in the cervical, axillary, and inguinal regions.  Complete blood count reveals anemia, thrombocytopenia, and leukocytosis.  Peripheral blood smear shows an increased number of small, mature-appearing, abnormal lymphocytes, which express CD20 and kappa light chains.  During treatment, the patient receives an agent that directly binds and inhibits BCL-2 protein.  Which of the following is the most likely effect of this therapy on the abnormal cells?

Quizplus · Accepted Answer

This patient's lymphadenopathy, splenomegaly, and increased number of mature lymphocytes in the blood that express B-cell markers (CD20⁺, kappa light chains) indicate chronic lymphocytic leukemia (CLL). This disease is characterized by the progressive accumulation of mature B cells in hematopoietic tissues (leading to anemia, thrombocytopenia, lymphadenopathy, and splenomegaly) and peripheral blood (leading to leukocytosis) due to genetic mutations that lengthen B-cell survival. In most cases of CLL, B-cell survival is promoted by the overexpression of BCL-2 on the mitochondrial membrane. BCL-2 is an antiapoptotic protein that prevents stress signals from triggering the intrinsic apoptotic cascade, which is mediated by the release of cytochrome c from the mitochondria and the subsequent activation of caspases. Treatment of CLL with BCL-2 inhibitors (eg, venetoclax) makes tumor cells more sensitive to stress signals (eg, chemotherapy) by increasing the activation of caspases, which leads to cell death. (Choice A) Bortezomib, a proteasome inhibitor that prevents the destruction of ubiquinated intracellular proteins, can be used against neoplasms that generate excessive amounts of protein (eg, multiple myeloma). (Choice B) Because cancer cells produce new antigens (neoantigens) not seen in normal cells, they generally have mutations that allow them to evade cytotoxic T-cell detection. Immune checkpoint inhibitors, such as antibodies against PD-1 (eg, pembrolizumab) or CTLA-4, prevent cancer cells from evading cytotoxic T-cell detection. (Choice D) Olaparib inhibits poly-ADP ribose polymerase, the enzyme that mediates the repair of single-strand DNA breaks. It is often used to treat breast, ovarian, or prostate cancer in individuals with BRCA mutations. (Choice E) Many forms of chemotherapy target rapidly dividing cells by inhibiting DNA replication during S phase (eg, purine analogs). BCL-2 does not mediate DNA replication or repair. (Choice F) Rituximab is a monoclonal antibody against the B-cell surface marker CD20. Although it is often used for CLL, it mediates cell death by binding to the B-cell surface (antibody-mediated cytotoxicity). Educational objective: Chronic lymphocytic leukemia is associated with overexpression of BCL-2, an anti-apoptotic protein, on the mitochondrial membrane. Treatment with a BCL inhibitor causes cancer cell death by promoting cytochrome c release from the mitochondria, which subsequently activates caspases. __________ References: The Bcl-2 apoptotic switch in cancer development and therapy. (http://www.ncbi.nlm.nih.gov/pubmed/17322918)

A 70-Year-Old Man Develops Progressive Fatigue and Easy Bruising