Abstract
Simple SummaryDiffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Despite the genetic heterogeneity of the disease, most patients are initially treated with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), but relapse occurs in ~50% of patients. One of the hallmarks of DLBCL is the occurrence of genetic events that inhibit apoptosis, which contributes to disease development and resistance to therapy. These events can affect the intrinsic or extrinsic apoptotic pathways, or their modulators. Understanding the factors that contribute to inhibition of apoptosis in DLBCL is crucial in order to be able to develop targeted therapies and improve outcomes, particularly in relapsed and refractory DLBCL (rrDLBCL). This review provides a description of the genetic events inhibiting apoptosis in DLBCL, their contribution to lymphomagenesis and chemoresistance, and their implication for the future of DLBCL therapy.Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discusses their implication for the future of DLBCL therapy.
Highlights
The intrinsic pathway is triggered by cellular stress, including DNA alteration, that leads to mitochondrial permeabilization and release of pro-apoptotic factors, while the extrinsic pathway is triggered by ligands binding to death receptors and subsequent activation of the death-inducing signaling complex (DISC)
Other rare genetic events directly involving nuclear factor kappa beta (NF-kB) include chromosome 10q24 rearrangements that lead to loss of the 30 -end of NFKB2 and constitutive protein activation [154], and amplifications of REL, which are mostly seen in germinal center B cell-like (GCB) Diffuse large B cell lymphoma (DLBCL) [9]
DLBCL genetically reprograms itself to inhibit apoptosis. This inhibition of apoptosis is a consequence of genetic events leading to dysregulation of several interacting pathways that modulate intrinsic and extrinsic apoptosis (Table 2)
Summary
Departments of Medicine and Oncology, Jewish General Hospital, Montreal, QC H3T 1E2, Canada. One of the hallmarks of DLBCL is the occurrence of genetic events that inhibit apoptosis, which contributes to disease development and resistance to therapy. These events can affect the intrinsic or extrinsic apoptotic pathways, or their modulators. Understanding the factors that contribute to inhibition of apoptosis in DLBCL is crucial in order to be able to develop targeted therapies and improve outcomes, in relapsed and refractory. This review provides a description of the genetic events inhibiting apoptosis in DLBCL, their contribution to lymphomagenesis and chemoresistance, and their implication for the future of DLBCL therapy. Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma
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