Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

Abstract

Diffuse large B-Cell lymphoma is the most common subtype of non-Hodgkin lymphoma in the West. In Brazil, it is the fifth cause of cancer, with more than 55,000 cases and 26,000 deaths per year. At Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo -HCFMUSP, diffuse large B-Cell lymphoma represents 49.7% of all non-Hodgkin lymphoma cases. Initially, the classification of non-Hodgkin lymphoma was based on morphology, but advances in immunology and molecular medicine allowed the introduction of a biological classification for these diseases. As for other cancers, non-Hodgkin lymphoma involves patterns of multifactorial pathogenesis with environmental factors, as well as genetic, occupational and dietary factors, contributing to its development. Multiple lesions involving molecular pathways of B-cell proliferation and differentiation may result in the activation of oncogenes such as the BCL2, BCL6, and MYC genes and the inactivation of tumor suppressor genes such as p53 and INK4, as well as other important transcription factors such as OCT-1 and OCT-2. A dramatic improvement in survival was seen after the recent introduction of the anti-CD20 monoclonal antibody. The association of this antibody to the cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) regimen has increased overall survival of diffuse large B-Cell lymphoma and follicular lymphoma patients by 20%. However, 50% of all diffuse large B-Cell lymphoma patients remain incurable, creating a demand for more research with new advances in treatment. Thus, it is important to know and understand the key factors and molecular pathways involved in the pathogenesis of diffuse large B-Cell lymphoma.

Suspected malignant transformation of B lymphocytes in the equine cornea from immune‐mediated keratitis

“…Diffuse large B‐cell lymphoma in humans is the most commonly diagnosed malignant lymphoma accounting for 30–40% of all non‐Hodgkin lymphomas . Subtypes of DLBCL are classified based on morphologic as well as immunologic and molecular data such as IHC, flow cytometry, cytogenetic assays, PARR, and gene signature by microarray . The majority of cases originate from lymph nodes, although up to 40% originate from extranodal sites including OALs which represent 2% of all lymphomas …”

Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin

“…To investigate the role of P4HA2 in human DLBCLs, we analyzed the expression of P4HA2 and compared it with that of Carabin in the same DLBCL tissues ( Figure 1A; supplemental Table 1) by western blotting (supplemental Figure 8). In .50% cases ( DLBCL 1,2,6,7,9,12,13,14,15,16, and 18; control 2, 3, and 4), there is a negative correlation between P4HA2 and Carabin. Although most cells are B-lymphoma cells in DLBCL tissue, the DLBCL tissues might contain contaminating fibroblasts that express high levels of P4HA2.…”

“…1 Non-GCB DLBCL is the most aggressive subtype and shows features of constitutive B-cell receptor (BCR)activated signaling and concomitant activation of the antiapoptotic NF-kB pathway. [2][3][4] The BCR signal pathway is indispensable for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting plasma cells. 5,6 BCR signaling is also a key driver of certain B-cell malignancies including DLBCL.…”

“…(J) SU-DHL-6 cell-expressed P306A mutant of Carabin has the lowest kinase activity of Erk. Cells depicted as in panel I were stimulated with PMA (40 ng/mL) for 10 min (1) or not(2). Cell lysates were analyzed using an anti-phospho Erk antibody.…”

“…Knockdown of Carabin abolishes the inhibition of Erk1/2 kinase activity by suppression of P4HA2. SU-DHL-4 (D), SU-DHL-6 (E), and NU-DUL-1 (F) cells were stimulated with PMA (40 ng/mL) for 30 minutes (1) or not(2), and then analyzed by immunoblotting for the indicated proteins. (G-I) P4HA2 promotes B-lymphoma cell proliferation in vivo depending on Carabin.…”