Mouse models of diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies

Targeting ATM-deficient CLL through interference with DNA repair pathways

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world and accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin lymphomas. The median age at diagnosis is 72 years. During recent years numerous genetic aberrations have been identified that are associated with an aggressive course of the disease and resistance against genotoxic chemotherapies. The DNA damage-responsive proapoptotic ATM-CHK2-p53 signaling pathway is frequently mutationally inactivated in CLL either through large deletions on chromosome 11 q (ATM) or 17p (TP53), or through protein-damaging mutations. Here, we focus on the role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis. We further discuss novel therapeutic concepts for the targeted treatment of ATM-defective CLLs. We specifically highlight the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones. Lastly, we briefly discuss the current state of genetically engineered mouse models of the disease and emphasize the use of these preclinical tools as a common platform for the development and validation of novel therapeutic agents

New murine models of aggressive lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive lymphoma and has traditionally been subdivided into germinal center B cell-like and activated B cell-like DLBCL, using transcriptome profiling. The recent characterization of the genomic landscape of DLBCL revealed the identity of at least five molecularly-defined subclusters of DLBCL. Intriguingly, these different clusters display a different response to frontline, anthracycline-based chemo-immune therapy. Moreover, multiple, potentially actionable genomic aberrations have been identified in these clusters, including EZH2, CREBBP/EP300, and KMT2D mutations, BCL2 overexpression, PTEN inactivation, CD274 rearrangements and others. With this genomic understanding, it is possible to develop autochthonous mouse models, which capture this genomic complexity. These models can serve as pre-clinical platforms to devise molecularly targeted therapeutic intervention strategies. Here, we review the available mouse models of aggressive lymphoma and indicate which compound-mutant mice may be desirable tools to further advance the field of translational lymphoma research

Rewired NF kappa B signaling as a potentially actionable feature of activated B-cell-like diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B-cell-like phenotype (GCB) and an activated B-cell-like phenotype (ABC). Particularly ABC-DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo-immune therapy. Through the availability of novel experimental technologies, such as next-generation sequencing and cutting-edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC-DLBCL. Currently, a picture is emerging which suggests that ABC-DLBCL critically depends on sustained activity of the NF kappa B pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B-, CARD11-, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC-DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non-physiological NFjB activity and repressing anti-apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials

DNA damage pathways and B-cell lymphomagenesis

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

ATM Deficiency Is Associated with Sensitivity to PARP1-and ATR Inhibitors in Lung Adenocarcinoma

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. (C) 2017 AACR

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3 mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. SIGNIFICANCE: We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (similar to 40%), with a therapeutic response to specific DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefit from a DNA-PKcs-inhibitory therapy. (C) 2014 AACR