Foundations · Year 1 · from Foundations
Case 1: Follicular Lymphoma (BCL2 Overexpression)
Clinical Image
Source: Wikipedia - Follicular lymphoma - CC BY-SA 3.0
Case Presentation
A 62-year-old woman presents with painless cervical lymphadenopathy noticed while showering. She has no fever, night sweats, or weight loss. Physical examination reveals multiple rubbery, non-tender lymph nodes in the cervical, axillary, and inguinal regions. CT scan shows widespread lymphadenopathy above and below the diaphragm. Excisional lymph node biopsy reveals follicular lymphoma grade 1-2. Cytogenetic analysis demonstrates the characteristic t(14;18)(q32;q21) translocation. This translocation places the BCL2 gene under control of the immunoglobulin heavy chain enhancer, resulting in marked overexpression of the anti-apoptotic Bcl-2 protein. The hematologist explains that normally, B cells in germinal centers that fail to successfully rearrange their immunoglobulin genes or that produce self-reactive antibodies undergo apoptosis. With Bcl-2 overexpression, these cells resist apoptosis and accumulate, eventually acquiring additional mutations that drive lymphomagenesis. Given her asymptomatic, advanced-stage disease, a watch-and-wait approach is initially adopted. Years later, when she develops symptoms, she is treated with rituximab plus bendamustine. More recently, venetoclax, a BH3 mimetic that specifically inhibits Bcl-2, has become available for Bcl-2-dependent malignancies.
Key Learning Points
- Bcl-2 is an anti-apoptotic protein that prevents mitochondrial outer membrane permeabilization (MOMP) by sequestering pro-apoptotic Bax and Bak; its overexpression blocks the intrinsic apoptotic pathway
- The t(14;18) translocation, discovered in follicular lymphoma, established that blocking cell death (not just promoting proliferation) is an oncogenic mechanism
- Understanding Bcl-2's mechanism led to development of BH3 mimetics like venetoclax, which bind Bcl-2 and release Bax/Bak to trigger apoptosis, representing targeted restoration of cell death