Aggressive lymphomas with MYC and BCL2 and/or BCL6 translocations ("double hit" lymphomas, DHL) represent a distinct diagnostic category in the updated World Health Organization (WHO) classification.
The possibility of combining antisense therapy such as BCL-2 antisense with chemotherapy will probably provide an interesting means of overcoming tumour cell resistance to chemotherapy in lymphoma and a range of other high BCL-2 expressing malignancies.
The consistent finding of the BCL-2 protein in lymphomas with testicular localisation may support the clinical observation that these lymphomas are a separate entity.
Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin.
The t(14;18) chromosomal translocation that results in the juxtaposition of the bcl-2 proto-oncogene with the heavy chain JH locus is a common cytogenetic abnormality in human lymphoma.
Molecular genetic analysis of these two cases revealed clonal gene rearrangement of the IGH locus but only germline configuration of the BCL2 oncogene at 18q21 when probes and conditions that usually identify BCL2 rearrangement in lymphomas were used.
These results demonstrate: 1) bcl-2 protein is expressed in a small portion of cutaneous B-cell lymphomas; 2) bcl-2 protein expression is significantly more frequent in secondary than in primary cutaneous B-cell lymphoma; 3) only approximately one-third of cases expressing the bcl-2 protein are characterized also by the t(14;18). bcl-2 protein expression might indicate that the cutaneous manifestation of the lymphoma represents a secondary spread from a node-based lymphoma.
BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression.
Breakpoints of a lymphoma case with bcl-2 gene rearrangement that did not show comigration of immunoglobulin (Ig) heavy chain joining (JH) fragment were cloned.
Our data support the notion that among gastrointestinal MALT lymphomas, t(14;18)-(IgH;Bcl-2) translocation clusters in HCV-positive patients sustaining the role of HCV infection in the lymphoma development.
Notably, Rac1 expression, and its interaction with Bcl-2, positively correlate with S70pBcl-2 levels in patient-derived lymphoma tissues and with advanced stage lymphoma and melanoma.
These results suggest that bcl-2 protein is broadly expressed in various hematopoietic neoplasms not restricted in t(14; 18) lymphomas and that germinal center cells may be involved in some arrest of bcl-2 protein expression at the posttranscriptional level.
Variant translocations leading to juxtaposing of the BCL2 with either the IGK or IGL gene have been recognized in B-cell malignant lymphoma, although they are rare.
The cytotoxicity of arsenic in the gsto1- and bcl-2-expressing chemoresistant and radioresistant LY-ar mouse lymphoma cell line, was compared with that of the LY-ar's parental cell line, LY-as.
Here we discuss the function of BCL-2 family proteins in germinal centre reactions, their deregulation in malignancies of germinal centre origin, and the potential for targeting BCL-2-related proteins therapeutically in lymphomas.
Indeed, previous studies using gene-targeted mice revealed that BCL-XL, but surprisingly not BCL-2, is critical for the development of c-MYC-induced pre-B/B lymphomas.
We conclude that the combination of rituximab and antisense-mediated down-regulation of BCL-2 has enhanced activity against human lymphoma, prolongs survival, and could cure mice bearing human lymphoma.