BCL6

WKP

Definition: The BCL6 gene is a proto-oncogene, that encodes for a zinc-finger transcriptional repressor acting on a series of target genes implicated in T and B cell maturation, cell cycle control, apoptosis or inflammation.

Its down regulation is necessary for the post-germinal center B cell maturation, whereas its expression is crucial for the germinal center formation.

BCL6 is a zinc-finger transcription repressor normally expressed exclusively within GC B cells, suggesting a critical role in the GC reaction.

BCL6 prevents terminal B-cell differentiation largely through repression of PRDM1.

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.

BCL6 is a transcription factor that has essential B-cell and T-cell roles in normal antibody responses.

Pathology

 BCL6 rearrangement

• BCL6 is involved in chromosomal translocations in diffuse large B-cell lymphoma (DBCL; including primary mediastinal B-cell lymphoma) and nodular lymphocyte predominant Hodgkin lymphoma.
• BCL6 rearrangements in B-cell lymphomas
  • nodal diffuse large cell lymphoma (nodal DLCL) (25%)
  • follicular lymphoma grade 3B (FL3B)
  • nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (48%) (12393409, 15339680)

 BCL6 expression

• BCL6 is expressed in follicular lymphoma and Burkitt’s lymphoma.
• The neoplastic T-cells of angioimmunoblastic T-cell lymphoma also express BCL6.

Diagnostic use

 DLBCL

• In the "cell of origin" classification of DLBCL, BCL6 is associated with the germinal centre subtype, which carries a good response to modern treatments.

Targeted therapy

Specific BCL6 antagonists, including small molecule inhibitors, have been developed.

These antagonists have demonstrated that DLBCL cells, in which BCL6 is transcriptionally active, are dependent on this gene for survival. BCL6 antagonists are active against primary DLBCL and may find future application in the treatment of lymphomas.

BCL6 rearrangement

The BCL6 gene is frequently disrupted at its 5’ noncoding region by 3q27 chromosomal translocations in B-cell lymphoma.

As a result of translocation, BCL6 is juxtaposed to reciprocal partners, such as the immunoglobulin (Ig) gene family. Besides the Ig loci, multiple non-Ig partners of the BCL6 translocation have been reported.

 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.

 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

• TFRC at 3q29 (MIM.190010)
• RHOH at 4p13 by t(3;4)(q27;p13) BCL6-RHOH (MIM.602037)
• SFRS3 at 6p21 by t(3;6)(q27;p21) BCL6-SFRS3 (SRP20) (MIM.603364)
• PIM1 at 6p21 by t(3;6)(q27;p21) BCL6-PIM1
• HIST1H4I at 6p22 by t(3;6)(q27;p22) BCL6-HIST1H4I (H4FM) (MIM.602833)
• ZNFN1A1 at 7p12 by t(3;7)(q27;p12) BCL6-ZNFN1A1 (MIM.603023)
• MYC (?) at 8q24 by t(3;8)(q27;q24)
• 9p13 at t(3;9)(q27;p13)
• POU2AF1 at 11q23 by t(3;11)(q27;q23)
• GAPDH at 12p13
• LCP1 at 13q14 by t(3;13)(q27;q14) BCL6-LCP1 (MIM.153430)
• HSPCA at 14q32
• 15q22 by t(3;15)(q27;q22)
• IL21R at 16p11 by t(3;16)(q27;p11) BCL6-IL21R (MIM.109565)
• MHC2TA at 16p13
• 17q11 by t(3;17)(q27;q11)
• EIF4A2 at 18p11
• GAS5/BCL6 fusion gene in B-cell lymphoma by t(1;3)(q25;q27) (18406879).

 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)

References

 Prognostic importance of BCL6 rearrangements in diffuse large B-cell lymphoma with respect to BCL6 protein levels and primary lymphoma site-reply. Tibiletti MG, Uccella S, Capella C. Hum Pathol. 2009 Apr 7. PMID: 19359028

 Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, Niitsu N, Jinnai I, Bessho M. The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 2008 Apr 15;182(2):144-9. PMID: 18406879