A lymph node biopsy from a 25-year-old shows a diffuse pattern of large blastoid cells with a 'starry sky' appearance, extremely high mitotic rate (Ki-67 ~100%), and immunophenotype: CD20+, CD10+, BCL6+, BCL2 negative, TdT negative, surface IgM+. FISH confirms t(8;14)(q24;q32). Which epigenetic and transcriptional mechanism downstream of c-MYC overexpression is most directly responsible for the near-100% proliferation index?

• A c-MYC heterodimerizes with MAX to directly transactivate E-box-containing target genes including CDK4, cyclin D2, and ribosomal protein genes, while repressing CDK inhibitors p21 and p27 ✓
• B Overexpressed c-MYC activates JAK-STAT3 signaling, leading to IL-6 autocrine loop sustaining S-phase entry
• C c-MYC causes BCL2 upregulation, reducing apoptosis and indirectly increasing the proportion of cells in S-phase
• D c-MYC represses miR-34a, increasing CDK6 translation and thereby accelerating G2-M transition

Explanation

Burkitt lymphoma is characterized by t(8;14), which juxtaposes c-MYC (8q24) with the IgH enhancer (14q32), causing massive c-MYC overexpression. c-MYC/MAX heterodimers bind E-box sequences (CACGTG) and activate transcription of genes driving cell growth and proliferation — including CDK4, cyclin D2, ornithine decarboxylase, and ribosomal protein genes — while suppressing CDK inhibitors p21/p27, accounting for the near-100% Ki-67. BCL2 is characteristically negative in Burkitt lymphoma (distinguishing it from double-hit lymphoma); high apoptosis rate creates the 'starry sky' pattern of tingible-body macrophages.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.