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Journal of Hematology & Oncology Aug 2021B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex... (Review)
Review
B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.
Topics: Animals; Antineoplastic Agents; B-Lymphocytes; Drug Discovery; Humans; Immunotherapy; Lymphoma, B-Cell; Molecular Targeted Therapy; Tumor Escape; Tumor Microenvironment
PubMed: 34404434
DOI: 10.1186/s13045-021-01134-x -
Cancer Dec 2018Emerging biologic subsets and new prognostic markers are significantly and adversely affecting curability after standard chemoimmunotherapy for aggressive B-cell... (Review)
Review
Emerging biologic subsets and new prognostic markers are significantly and adversely affecting curability after standard chemoimmunotherapy for aggressive B-cell lymphomas. The identification of concurrent MYC and B-cell CLL/lymphoma 2 (BCL2) deregulation, whether at a genomic or protein level, has opened a new era of investigation within the most common subtype of aggressive B-cell lymphomas. Double-hit lymphoma (DHL), defined as a dual rearrangement of MYC and BCL2 and/or B-cell CLL/lymphoma 6 (BCL6) genes, is an uncommon subset accounting for 5% to 7% of all diffuse large B-cell lymphomas (DLBCLs), and long-term survivors are rare. Double-expressor lymphoma (DEL), defined as overexpression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements, is not a distinct entity in the current World Health Organization classification but accounts for 20% to 30% of DLBCL cases and also has poor outcomes. There are many practical considerations related to identifying, determining the prognosis of, and managing DHL and DEL.
Topics: Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell; Prognosis; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Up-Regulation
PubMed: 30252929
DOI: 10.1002/cncr.31646 -
British Journal of Haematology Jun 2020Aggressive B-cell non-Hodgkin lymphoma (B-NHL) accounts for ≈60% of NHL in children/adolescents. In newly diagnosed Burkitt lymphoma and diffuse large B-cell lymphoma,... (Review)
Review
Aggressive B-cell non-Hodgkin lymphoma (B-NHL) accounts for ≈60% of NHL in children/adolescents. In newly diagnosed Burkitt lymphoma and diffuse large B-cell lymphoma, short intensive multiagent chemotherapy is associated with a five-year event-free survival of around 90%. Very few children/adolescents with aggressive B-NHL show a relapsed/refractory (r/r) disease. The outcome is poor, with cure rates <30%, and there is no standard of care. Rituximab-containing salvage regimens may provide a complete/partial response in 60-70% of cases. However, long-term survival is <10% for non-transplanted patients. Autologous or allogeneic haematopoietic stem cell transplant is, nowadays, the best option for responding patients, with survival rates around 50%. The benefit of autologous versus allogeneic HSCT is not clear. Numerous novel therapies for r/r B-NHL are currently being tested in adults, including next-generation monoclonal antibodies, novel cellular therapy strategies and therapies directed against new targets. Some are under investigation also in children/adolescents, with promising preliminary results.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Combined Modality Therapy; Cranial Irradiation; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Kaplan-Meier Estimate; Lymphoma, B-Cell; Male; Mediastinal Neoplasms; Prognosis; Recurrence; Risk Factors; Salvage Therapy; Therapies, Investigational; Treatment Outcome; Young Adult
PubMed: 32141616
DOI: 10.1111/bjh.16461 -
Blood Jan 2004Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and... (Comparative Study)
Comparative Study
Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 gene expression profiles using a cDNA microarray. Tissue microarray (TMA) blocks were created from 152 cases of DLBCL, 142 of which had been successfully evaluated by cDNA microarray (75 GCB, 41 ABC, and 26 type 3). Sections were stained with antibodies to CD10, bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. Expression of bcl-6 (P <.001) or CD10 (P =.019) was associated with better overall survival (OS), whereas expression of MUM1 (P =.009) or cyclin D2 (P <.001) was associated with worse OS. Cases were subclassified using CD10, bcl-6, and MUM1 expression, and 64 cases (42%) were considered GCB and 88 cases (58%) non-GCB. The 5-year OS for the GCB group was 76% compared with only 34% for the non-GCB group (P <.001), which is similar to that reported using the cDNA microarray. Bcl-2 and cyclin D2 were adverse predictors in the non-GCB group. In multivariate analysis, a high International Prognostic Index score (3-5) and the non-GCB phenotype were independent adverse predictors (P <.0001). In summary, immunostains can be used to determine the GCB and non-GCB subtypes of DLBCL and predict survival similar to the cDNA microarray.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cyclin D2; Cyclins; Female; Humans; Immunohistochemistry; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Prognosis; Protein Array Analysis; Proto-Oncogene Proteins c-bcl-2; Sensitivity and Specificity
PubMed: 14504078
DOI: 10.1182/blood-2003-05-1545 -
Trends in Biochemical Sciences Jan 2005Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB... (Review)
Review
Nuclear factor-kappaB (NF-kappaB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Activation of NF-kappaB mainly occurs via IkappaB kinase (IKK)-mediated phosphorylation of inhibitory molecules, including IkappaBalpha. Optimal induction of NF-kappaB target genes also requires phosphorylation of NF-kappaB proteins, such as p65, within their transactivation domain by a variety of kinases in response to distinct stimuli. Whether, and how, phosphorylation modulates the function of other NF-kappaB and IkappaB proteins, such as B-cell lymphoma 3, remains unclear. The identification and characterization of all the kinases known to phosphorylate NF-kappaB and IkappaB proteins are described here. Because deregulation of NF-kappaB and IkappaB phosphorylations is a hallmark of chronic inflammatory diseases and cancer, newly designed drugs targeting these constitutively activated signalling pathways represent promising therapeutic tools.
Topics: Animals; Drug Design; Gene Expression Regulation, Leukemic; Humans; I-kappa B Proteins; Inflammation; Lymphoma, B-Cell; NF-kappa B; Phosphorylation; Signal Transduction; Transcription Factor RelA
PubMed: 15653325
DOI: 10.1016/j.tibs.2004.11.009 -
Journal of Hematology & Oncology Jul 2019Lymphomas are a heterogeneous group of lymphoproliferative disorders, with unique clinical and biological characteristics that exhibit variable response to therapy.... (Review)
Review
Lymphomas are a heterogeneous group of lymphoproliferative disorders, with unique clinical and biological characteristics that exhibit variable response to therapy. Advances in chemo-immunotherapy have improved outcomes in a number of lymphoma subtypes; however, the prognosis for many patients with relapsed and refractory disease remains poor. Novel therapies including several small molecule inhibitors and chimeric antigen receptor T cells have been approved for the treatment of different lymphoma subtypes at relapse, changing the therapy landscape and further improving survival in many of these diseases. This has led to a focus on the development of new cellular therapy, antibody-based therapy, and small molecule inhibitors for relapsed and refractory disease that offer an alternative approach to cytotoxic chemotherapy. We will review these promising novel therapies and discuss their safety and efficacy in first in human studies.
Topics: Humans; Immunotherapy; Lymphoma, B-Cell
PubMed: 31345247
DOI: 10.1186/s13045-019-0752-3 -
Haematologica Feb 2014B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features.... (Review)
Review
B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities.
Topics: Chromosome Aberrations; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell; MicroRNAs; RNA, Neoplasm
PubMed: 24497559
DOI: 10.3324/haematol.2013.096248 -
The New England Journal of Medicine Jun 2002The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of...
BACKGROUND
The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival.
METHODS
Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index.
RESULTS
Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators.
CONCLUSIONS
DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.
Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Female; Gene Expression Profiling; Humans; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Analysis
PubMed: 12075054
DOI: 10.1056/NEJMoa012914 -
Hematological Oncology Dec 2021Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B-cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant... (Review)
Review
Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B-cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant B-cell pathophysiology, allowing better drug response as well as low toxicity. However, these multiple mechanisms also lead to drug resistance, which compromised the treatment outcome and needs to be solved urgently. This review focuses on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3, TRAF2, TRAF3, CARD11, MYD88, and CCND1 mutations) and related pathways (such as PI3K/Akt/mTOR, NF-κB, MAPK signaling pathways, overexpression of B-cell lymphoma 6, platelet-derived growth factor, toll-like receptors, and microenvironment, cancer stem cells, and exosomes) involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi. We have also reviewed the newly reported drug resistance mechanisms and the proposed potential treatment strategies (the next-generation BTKi, proteolysis-targeting chimera-BTK, XMU-MP-3, PI3K-Akt-mTOR pathway, MYC or LYN kinase inhibitor, and other small-molecule targeted drugs) to overcome drug resistance. The findings presented in this review lay a strong foundation for further research in this field.
Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Lymphoma, B-Cell; Molecular Targeted Therapy; Prognosis
PubMed: 34651869
DOI: 10.1002/hon.2933 -
Archives of Pathology & Laboratory... Nov 2018Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In... (Review)
Review
CONTEXT.—
Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In particular, chronic lymphocytic leukemia/small lymphocytic lymphoma is a very common malignancy in the Western hemisphere, and most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma have an indolent course and behavior. However, 2% to 8% of chronic lymphocytic leukemia/small lymphocytic lymphoma cases transform. Histiocytic sarcomatous transformation is rare and portends poor prognosis.
OBJECTIVE.—
To review the clinical features, morphology, and key points related to the differential diagnosis for histiocytic sarcoma. We discuss recent understanding of the biology underlying transformation.
DATA SOURCES.—
University of Michigan case and review of pertinent literature about histiocytic sarcoma and morphologic differential diagnosis.
CONCLUSIONS.—
Histiocytic sarcoma is a rare histiocytic neoplasm that can arise as a result of transdifferentiation from low-grade B-cell lymphomas, and has a wide differential diagnosis including other histiocytic/dendritic cell neoplasms, myeloid neoplasms, lymphomas, melanoma, and carcinoma. However, some key morphologic and immunohistochemical features allow for accurate classification.
Topics: Cell Transformation, Neoplastic; Diagnosis, Differential; Histiocytic Sarcoma; Humans; Lymphoma, B-Cell
PubMed: 30407858
DOI: 10.5858/arpa.2018-0220-RA