Genetic and Molecular Targets in Lymphoma
Genetic and Molecular Targets in Lymphoma
BCL-6 expressed at physiologic levels in germinal center (GC) modulates B-cell receptor (BCR)-mediated survival of lymphocytes and affinity maturation of immunoglobulins (Ig). The process of affinity maturation of Ig, that helps with creation of memory B cells and plasma cells, is a consequence of BCL-6-mediated genomic instability created by attenuating tumor suppressor TP53 gene and the DNA damage sensor ATR kinase functioning. Unlike in normal GC development, BCL-6 can be constitutively activated in lymphomas and promote lymphocyte proliferation and differentiation blockade. Identification of high BCL-6 expression by IHC is associated with superior disease-free survival (DFS) and progression-free survival (PFS) in various lymphomas when treated with anthracycline-based chemotherapy. Addition of rituximab to chemotherapy for treating BCL-6-positive lymphomas may not confer similar advantage as for the BCL-6-negative lymphomas, especially in DLBCL. Thus, to overcome the poor prognostic significance of BCL-6, targeted therapy against Bcl-6, capable of overcoming transcriptional repression and differentiation blockade in lymphomas is desirable. In lymphoma cell lines and xenograft mouse models, peptomimetic inhibitors and heat shock protein 90 (HSP90) inhibitors have shown promising BCL-6 inhibition and anti-lymphoma activity, which still needs to be confirmed in clinical trials.
BCL-6
BCL-6 expressed at physiologic levels in germinal center (GC) modulates B-cell receptor (BCR)-mediated survival of lymphocytes and affinity maturation of immunoglobulins (Ig). The process of affinity maturation of Ig, that helps with creation of memory B cells and plasma cells, is a consequence of BCL-6-mediated genomic instability created by attenuating tumor suppressor TP53 gene and the DNA damage sensor ATR kinase functioning. Unlike in normal GC development, BCL-6 can be constitutively activated in lymphomas and promote lymphocyte proliferation and differentiation blockade. Identification of high BCL-6 expression by IHC is associated with superior disease-free survival (DFS) and progression-free survival (PFS) in various lymphomas when treated with anthracycline-based chemotherapy. Addition of rituximab to chemotherapy for treating BCL-6-positive lymphomas may not confer similar advantage as for the BCL-6-negative lymphomas, especially in DLBCL. Thus, to overcome the poor prognostic significance of BCL-6, targeted therapy against Bcl-6, capable of overcoming transcriptional repression and differentiation blockade in lymphomas is desirable. In lymphoma cell lines and xenograft mouse models, peptomimetic inhibitors and heat shock protein 90 (HSP90) inhibitors have shown promising BCL-6 inhibition and anti-lymphoma activity, which still needs to be confirmed in clinical trials.
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