BCL6 is a zinc-finger transcription repressor normally expressed exclusively within GC B cells, suggesting a critical role in the GC reaction. Indeed, BCL6 null animals fail to generate GCs in response to antigen. The down-regulation of BCL6 may be necessary for normal GC B cells to further differentiate into memory B cells or plasma cells.

Pathology

 Chromosomal translocations involving the BCL6 gene on band 3q27 are the most common genetic abnormalities in DLBCL, occurring in 35% to 40% of cases. Although several chromosomes may partner with 3q27, the most common translocations involve the immunoglobulin heavy-chain promoter (IGH promoter), resulting in constitutive expression of this normally developmentally regulated gene.

 In diffuse large b-cell lymphoma (DLBCL), dysregulated constitutive expression of BCL6 may lead to maturation arrest and confer a proliferative advantage.

 Recent studies identify a mechanism whereby BCL6 may regulate GC formation and lymphomagenesis via down-regulation of p53.

 Investigators postulate that BCL6 functions normally to suppress p53-mediated apoptosis of GC B cells in response to DNA damage during the GC reaction.

 Constitutive expression of BCL6 might decrease the p53-mediated apoptotic response to DNA damage, promoting persistence of malignant clones. A recently developed BCL6 transgenic mouse provides further insight into the precise role of this gene in lymphomagenesis.

 BCL6 rearrangements occur primarily in de novo DLBCL.

 No uniform effect on prognosis has been observed, likely due to multiple other contributing factors, including differential biology of the partner chromosome, concomitant genetic defects, SHM, and unidentified molecular substructure.

Summary

 BCL6 rearrangements in B-cell lymphomas

• nodal diffuse large cell lymphoma (DLCL) (25%)
• follicular lymphoma grade 3B (FL3B)
• nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (48%) (#12393409#, #15339680#)

 translocation with Ig genes

• t(3;14)(q27;q32) (BCL6-IGH)
• t(2;3)(p12;q27) (BCL6-IGK)
• t(3;22)(q27;q11) (BCL6-IGL)

 fusion genes

• t(3;4)(q27;p13) BCL6-RHOH
• t(3;6)(q27;p21) BCL6-SRP20
• t(3;6)(q27;p22) BCL6-H4FM
• t(3;7)(q27;p12) BCL6-ZNFN1A1
• t(3;8)(q27;q24)
• t(3;9)(q27;p13)
• t(3;11)(q27;q23)
• t(3;13)(q27;q14) BCL6-LCP1
• t(3;15)(q27;q22)
• t(3;17)(q27;q11)
• t(3;16)(q27;p11) BCL6-IL21R

 BCL6 rearrangements in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (48%) (#15339680#)

• t(3;22)(q27;q11) targeting immunoglobulin (IG) alpha chain locus (#15339680#)
• complex t(3;7;3;1) involving the 7p12/Ikaros gene region (#15339680#)
• t(3;9)(q27;p13) affecting an unknown gene in vicinity of PAX5 (#15339680#)
• t(3;4)(q27;q32) (#15339680#)

 BCL6 rearrangements in follicular lymphoma grade 3B (FL3B)(centroblasts) (55%)

 BCL6 mutations in

• pulmonary lymphoproliferative disorders(#15153535#)
  • mucosa-associated lymphoid tissue (MALT) lymphoma (40%) (#15153535#)
  • HIV-related (100%) (#15153535#)
  • EBV-related (40%) (#15153535#)
  • virus-negative lymphocytic interstitial pneumonia (LIP) (30%) (#15153535#)