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.