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DNA damage pathways and B-cell lymphomagenesis

Knittel, Geroa,b; Rehkämper, Tima,b; Nieper, Pascala,b; Schmitt, Annaa,b; Flümann, Rutha,b,c; Reinhardt, H., Christiana,b,c,d

Current Opinion in Hematology: July 2018 - Volume 25 - Issue 4 - p 315–322
doi: 10.1097/MOH.0000000000000433

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.

aDepartment I of Internal Medicine, University Hospital of Cologne

bCologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD)

cCenter of Integrated Oncology (CIO), University Hospital of Cologne

dCenter of Molecular Medicine, University of Cologne, Cologne, Germany

Correspondence to Gero Knittel, Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931 Cologne, Germany. E-mail:; H. Christian Reinhardt, Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931 Cologne, Germany. E-mail:

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