What is the molecular biology of DLBCL?

Updated: Jun 12, 2019
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Numerous genetic and molecular changes accumulate through a multistep process leading to the selective growth advantage of a malignant clone. B-cell lymphomas arise at various stages of B-cell development. Under normal circumstances, a pro-B cell undergoes various stages of maturation that include (1) the recombination of the V, D, and J gene segments necessary for assembling of the immunoglobulins’ heavy and light chains; (2) somatic hypermutation; and (3) immunoglobulin-class switching. During the process of V(D)J recombination (regulated by the recombination activating genes 1 [RAG1] and 2 [RAG2] enzymes) and somatic hypermutation/immunoglobulin-class switching (regulated by the activation-induced cytidine deaminase [AID] enzyme) phases, multiple DNA alterations occur and normal B cells are susceptible to the development of undesirable chromosomal translocations or gene mutations, leading to the development of B-cell lymphoma. [55]

Abnormalities in the process of B-cell maturation lead to the development of lymphoid malignancies. The type of mutation(s) and the stage of lymphoid maturation at the time of genetic aberration(s) play a role in the type of lymphoma that may develop in a given patient. [56] Subtypes of diffuse large B-cell lymphoma (DLBCL) arise from genetic alterations occurring during the process of B-cell differentiation/maturation and, in general, are characterized by a blockage of the programmed cell death process (ie, up-regulation of Bcl-2, loss of Bcl-6 function, p53 deletion/mutation), an increase in cell proliferation (eg. increase in nuclear factor kappa B [NFkB], up-regulation of c-Myc), or impaired terminal differentiation (ie, defective Blimp-1 function). Specific genetic alteration(s) or protein expression/function deregulation varies depending on the subtype of DLBCL.

Several oncogenic pathways have been identified in DLBCL (B-cell receptor [BCR] signaling pathway, constitutive activation of NFkB activity pathways, and deregulation of the Bcl-6/apoptosis pathway); however, only one pathway appears to play a pivotal role in the biology of distinct types of DLBCL (ie, germinal center B-cell [GCB] vs activated B-cell [ABC] DLBCL). [55]


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