Do BCL6 (B-cell lymphoma 6) and BCL2 (B-cell lymphoma 2) rely on each other and cMyc (v-myc avian myelocytomatosis viral oncogene homolog) for expression in Follicular Lymphoma (FL)?

BCL6, BCL2, and cMYC Expression in Follicular Lymphoma

In follicular lymphoma (FL), BCL6 and BCL2 expression are independent events with separate genetic mechanisms, while MYC rearrangements typically occur as secondary events during disease progression rather than being dependent on BCL2 or BCL6 expression. 1

Genetic Mechanisms in Follicular Lymphoma

BCL2 Expression

• Approximately 85% of FL cases harbor the t(14;18)(q32;q21) translocation involving IGH::BCL2 1
• This translocation is the characteristic genetic hallmark of "classic FL" 2
• Variant translocations can also occur:
  • t(2;18)(p12;q21) involving IGK::BCL2
  • t(18;22)(q21;q11.2) involving IGL::BCL2 1

BCL6 Expression

• BCL6 rearrangements occur in a subset of FL cases (approximately 10-15%)
• BCL6 rearrangements are more common in BCL2-negative FL 3
• The 3q27 region containing BCL6 can be involved in various translocations 1

Relationship Between BCL2 and BCL6

• BCL2 and BCL6 rearrangements typically occur through independent mechanisms
• There is no evidence that the presence of one translocation in the immunoglobulin heavy chain locus influences the expression of the other translocated gene 4
• In BCL2-negative FL cases, BCL6 rearrangements and/or high BCL6 expression may serve as an alternative oncogenic mechanism 3
• Some FL cases can have both BCL2 and BCL6 rearrangements (BCL2/BCL6 double-rearranged FL) 5

MYC Involvement in FL

• MYC rearrangements are rare in initial FL diagnosis but can occur during transformation 6
• MYC activation is typically a secondary event in FL progression rather than an initiating event 6
• Approximately 10% of transformed FLs acquire a MYC translocation in addition to the original BCL2 translocation 4

Clinical and Prognostic Implications

BCL6-Rearranged FL

• BCL6-rearranged FL shows distinct clinicopathological features:
  • Lower rates of advanced clinical stage
  • Less bone marrow invasion
  • Less disease progression
  • Trend toward favorable progression-free survival
  • Higher rates of grade 3A and MUM1 expression 5

Double-Hit and Triple-Hit Lymphomas

• FL can transform into aggressive double-hit lymphomas with concurrent activation of MYC and BCL2 6
• These cases have poorer prognosis and require more aggressive treatment approaches 1
• Double and triple-hit lymphomas are rare in pediatric populations but more common in adolescent and young adult patients 1

Diagnostic Considerations

• FISH testing is essential for detecting BCL2, BCL6, and MYC rearrangements 1
• Immunohistochemistry helps characterize expression patterns:
  • BCL2 expression is typically positive in t(14;18)-positive FL
  • BCL6 is variably expressed and may be high in BCL2-negative FL
  • MYC expression should be assessed, especially in cases with aggressive features 1

Molecular Mechanisms

• Transcriptional control of BCL2 and c-MYC involves different regulatory elements:
  • In BCL2-translocated FL, CRE and Cdx sites in the BCL2 promoter are occupied on the translocated alleles
  • In MYC-translocated cases, nuclear factor kappaB sites are occupied on the translocated MYC allele 4
• There is no direct transcriptional co-regulation between BCL2 and MYC in FL 4

In summary, while BCL2, BCL6, and MYC all play important roles in FL pathogenesis and progression, they operate through distinct molecular mechanisms and do not directly rely on each other for expression. The acquisition of MYC rearrangements in FL with pre-existing BCL2 translocations represents a progression event rather than an interdependent expression mechanism.