DNA damage pathways and B-cell lymphomagenesis

Abstract

Purpose of review Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity. Recent findings The results of several large lymphoma genome sequencing projects have recently been reported, including CLL, T-PLL and DLBCL. We align these discoveries with proposed mechanisms of mutation acquisition in B-cell lymphomas. Moreover, novel autochthonous mouse models of CLL have recently been generated and we discuss how these models serve as preclinical tools to drive the development of novel targeted therapeutic interventions. Lastly, we highlight the results of early clinical data on novel compounds targeting defects in the DNA damage response of CLL with a particular focus on deleterious ATM mutations. Summary Defects in DNA repair pathways are selected events in cancer, including lymphomas. Specifically, ATM deficiency is associated with PARP1- and DNA-PKcs inhibitor sensitivity in vitro and in vivo.

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

“…In summary, this review indicates the potential opportunities to combine C-NHEJ and A-EJ inhibitors with chemoradiation treatment modalities for inducing synthetic lethal vulnerability in hematologic malignant cells with up-regulation of these pathways. [203,225] MV4-11 cells (AML cell line) ATM inhibition radiosensitized MV4-11 leukemia cells [182] P39 and MOLM-13 cell lines (MDS cell lines) ATM inhibition increase radiosensitization of MDS cells [182] EBV-driven Burkitt lymphoma cells Inhibition of EBV replication through inhibition of KAP1 phosphorylation [205] Ramos cells Prevention of ATM auto-phosphorylation and potentiation of etoposide-induced apoptosis [226] Cisplatin-resistant MCL cell line (JeKo-1/DDP) Enhanced cisplatin-induced DNA damage [206] HCL cell line MLMA Induction of apoptosis through inhibiting NF-κB pathway [207] KU-59403 Jurkat cells Showing higher potency, tissue distribution, and efficacy over KU-55933 [225] AZD0156 AML exhibits therapeutic potential in a mouse model of MLL-rearranged AML [227] KU-60019 Human B cell lymphoma cell lines, lymphoblastoid cell lines, and myeloma lines KU-60019 potentiates bendamustine activity [212] MCL cell lines KU60019 synergizes the antineoplastic effect of romidepsin [228] Caffeine (Inhibitor of both ATM and ATR)…”

“…The promoting effect of DNA-PK inhibitors on radiation and topoisomerase II inhibitors has been demonstrated in several hematologic cancers, such as CLL, ALL, CML, AML, APL, and adult T-cell leukemia/lymphoma [ 181 ]. Given the relationship between ATM deficiency and sensitivity to DNA-PKcs inhibitors, the effects of these inhibitors on lymphoma have been investigated [ 182 ].…”

TEOA Inhibits Proliferation and Induces DNA Damage of Diffuse Large B-Cell Lymphoma Cells Through Activation of the ROS-Dependent p38 MAPK Signaling Pathway

“…DLBCL is a heterogeneous disease characterized by high levels of genomic instability (Barlow et al, 2013), and activation of DNA damage repair pathways, including the activation of nucleotide excision DNA repair (NER) and DNA damage response kinases (Shaheen et al, 2011;Gu et al, 2015). Studies have shown that inhibition of the process of DNA damage repair, such as inhibitors of kinase WEE1, could effectively prevent the progress of DLBCL (Knittel et al, 2018;Jong et al, 2020). Furthermore, it has been demonstrated that NER pathway related proteins were usually overexpressed in CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) resistant DLBCL cells.…”

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

“…As summarized in Fig. 1, there are multiple mechanisms by which DDR pathways are deregulated in B-cell lymphomas [23]. The vast majority of lymphomas derive from germinal center (GC) B-cells or Bcells that have passed through the GC [24].…”