Abstract
Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient’s population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.
Highlights
Diffuse Large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype, and yet 40% of patients are resistant to current therapies [1,2,3], which are still based on the induction of exogenous DNA damage with anthracycline-based chemotherapy regimens representing the standard of care [1,2,3]
Replicative and oxidative stress biomarkers identify poor prognosis subsets of double expresser DLBCL In order to investigate the relationship between cell of origin (COO) classification, MYC/BCL-2 status, and replicative/oxidative stress biomarkers, we first profiled two independent case series of chemoimmunotherapy-treated DLBCL with T-gene expression profiling (GEP), fluorescence in situ hybridization (FISH), and immunohistochemistry: a discovery cohort from the DLC04 study [34], and a validation cohort of patients treated in real-life clinical practice
We demonstrated that: 1) expression levels of the DNA damage marker γH2AX and the oxidative DNA damage marker 8-OHdG are tightly associated, suggesting that oxidative stress could be a major source of inherent DNA damage contributing to constitutive DNA damage response (DDR) activation in DLBCL (Fig. 2); 2) Dual positivity for γH2AX and 8-OHdG is significantly associated with adverse outcome in the MYC/BCL-2 positive DLBCL subset
Summary
Hodgkin lymphoma (NHL) subtype, and yet 40% of patients are resistant to current therapies [1,2,3], which are still based on the induction of exogenous DNA damage with anthracycline-based chemotherapy regimens representing the standard of care [1,2,3]. Besides the COO, overexpression or genomic rearrangements of the MYC and BCL-2 oncogenes are powerful negative prognostic factors in DLBCL [13, 14]. Due to the fact that concurrent MYC and BCL-2 rearrangements enrich for a patient’s population characterized by refractoriness to standard anthracycline-based chemotherapy, these lymphomas are classified as a separate disease entity (HG-BCL w/DH) [15] and currently treated with more intensive chemotherapy regimens, representing a major unmet need in lymphoma therapy [16, 17].
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