We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanism-based treatments for lymphoma.
Previous studies have suggested that NF-kappaB activity is suppressed in germinal center and lymphoma B cells that express high levels of BCL-6, and yet the reason for this is unknown.
High grade B-cell lymphoma (HGBCL) by WHO 2016 classification requires rearrangements of MYC and BCL2 and/or BCL6, practically covering the so called "double-hit" or "triple hit" lymphomas.
As BCL6 plays a central role in the pathogenesis of diffuse large B-cell lymphoma, we predict that targeting BCL6 transcriptional repression complexes in malignant B-cells may constitute a novel form of transcription therapy for lymphomas and possibly other tumors.
The BCL-6 protein is a potent transcriptional repressor which presumably controls lymphocyte differentiation and induces lymphomas by regulating the expression of key downstream target genes.
High-grade B-cell lymphomas (HGBLs) with MYC and BCL2 and/or BCL6 rearrangements, so-called "double-hit" lymphomas (HGBL-DH), are aggressive lymphomas that form a separate provisional entity in the 2016 revised World Health Organization Classification of Lymphoid Tumors.
Lymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL-2 protein overexpression, classified as double-hit (DHL) or double-expressor (DEL) lymphomas, respectively, are associated with poorer response to standard immunochemotherapy.
Rearrangement of the bcl-6 gene correlated with a favorable clinical outcome in DLLC and may thus serve as a prognostic marker in patients with this form of malignant lymphoma.
The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.
Immunophenotypic and genotypic markers used to suggest a FCC origin for a lymphoma (bcl-6 and CD10 expression, lack of CD138 expression, bcl-2 rearrangements [R]) or to subdivide DLBCL (bcl-2 expression, bcl-6 R) were therefore investigated in 22 FL and 44 DLBCL using paraffin section immunostains and Southern blot/polymerase chain reaction analysis.
The median cytogenetic complexity score was 2.5 (range, 0 to 14) in 14 evaluable mature aggressive lymphomas with an immunoglobulin gene partner for MYC in 9/14 and for BCL6 in 7/14 cases.
Double-color FISH with IgH (Y6) and BCL6 (cosB5-1) showed fusion of BCL6 and IgH genes on der(3)t(3;14) in all nine patients, suggesting that der(3) may play a critical role in the development of lymphoma carrying complex as well as standard t(3;14) translocations.
Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.
Patients with both MYC and BCL2 CNA had similar outcomes to those with classic double hit lymphoma or protein double expression lymphoma (MYC and BCL2/BCL6 coexpression).
Several experiments and mouse models mimicking BCL6 translocation occurring in human lymphoma have demonstrated the oncogenic role of BCL6 and constitute a rational to consider BCL6 as a new therapeutic target in NHL.
We demonstrate that lymphoma cell lines and majority of NHL tumor specimens expressed BCL6 mRNA predominantly from the rearranged allele that may come under the control of various partner gene promoters.