Apoptosis resistance and response to chemotherapy in primary nodal diffuse large B‐cell lymphoma

Abstract

Diffuse large B-cell lymphomas (DLBCL) represent the most common type of adult malignant lymphoma in western countries and are treated with high dose combination chemotherapy. Although initially the majority of patients respond to this therapy, many do not achieve complete remission and others experience an early relapse. Several studies have shown that prediction of the clinical response to chemotherapy is possible before the start of chemotherapy treatment. Apparently, DLBCL are intrinsically either resistant or sensitive to chemotherapy-induced cell death. Differences in functional integrity of the apoptosis cascade are an important factor predicting outcome in DLBCL. In this review we discuss the possible mechanisms leading to intrinsic resistance to apoptosis and provide an explanation why strong differences in apoptosis sensitivity between DLBCL are observed. Subsequently we will focus on how differences in this intrinsic apoptosis resistance provide an explanation for the variable response to combination chemotherapy and how this can be used for further therapy tailoring.

A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

“…5 However, processes that occur during DLBCL transformation inhibit these apoptotic cascades, provoking intrinsic resistance to chemotherapyinduced cell death. 37 Caspase-9 apoptosis, for example, can be inhibited by defective p53 activation or Bcl-2 protein overexpression (Bcl-2 or Mcl-1), whereas caspase-8 is blocked by death receptor mutations or c-FLIP overexpression in DLBCL. 5,37 For this reason, experimental therapies presently undergoing clinical trials for chemotherapy-refractory DLBCLs are aimed at restoring caspase-9-or caspase-8-dependent apoptosis.…”

“…37 Caspase-9 apoptosis, for example, can be inhibited by defective p53 activation or Bcl-2 protein overexpression (Bcl-2 or Mcl-1), whereas caspase-8 is blocked by death receptor mutations or c-FLIP overexpression in DLBCL. 5,37 For this reason, experimental therapies presently undergoing clinical trials for chemotherapy-refractory DLBCLs are aimed at restoring caspase-9-or caspase-8-dependent apoptosis. 5 E7123, in contrast, is capable of inducing cell death by a mechanism that avoids these 2 major apoptotic pathways, representing a possible alternative to treat those DLBCL patients resistant to current therapies.…”

Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death

“…3,4 We propose that expression and cell-surface localization of gal-3, and interaction of cell-surface gal-3 with CD45 to regulate CD45 phosphatase activity, is a novel mechanism of apoptosis resistance in DLBCL. In the present study, when the interaction of gal-3 and CD45 on DLBCL cells was disrupted by removing cell-surface gal-3 with GCS-100, cells were sensitized to apoptosis induced by a variety of agents (Figure 3).…”

“…Cell-surface proteins on SUDHL-6 cells treated with or without GCS-100 were cross-linked with the nonreducible crosslinking agent BS. 3 As shown in Figure 7A, BS 3 cross-linked CD45 from whole-cell lysates of control cells migrated as a highmolecular-weight smear, while BS 3 cross-linked CD45 from lysates of cells pretreated with GCS-100 lacked the highest molecularweight bands seen in the control cells. Similarly, immunoprecipitated cross-linked CD45 from control SUDHL-6 cells contained highmolecular-weight bands that were not detectable in cross-linked CD45 immunoprecipitated from GCS-100-treated cells.…”

“…1 DLBCL is the most commonly diagnosed non-Hodgkin lymphoma 2 and is an aggressive malignancy with a survival rate of ϳ 60%, partly because DLBCL cells become resistant to apoptosis induced by chemotherapy drugs. 3,4 There are at least 3 molecular subtypes of DLBCL that reflect the biology of the B cell of origin. 4,5 Despite the prevalence of DLBCL, and perhaps because of DLBCL heterogeneity, there is no known canonical mechanism of apoptosis resistance for the majority of DLBCL.…”