The DNA damage response pathway in normal hematopoiesis and malignancies

In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations. Besides favoring tumor formation and progression, molecular defects that directly or indirectly inactivate certain DDR pathways can provide a therapeutic opportunity, since a reduced ability to repair DNA lesions renders hemopoietic malignancies vulnerable to genotoxic drugs acting also through synthetic lethal interactions. Here, we discuss the essential role of DDR in HSC maintenance and protection against leukemogenesis, and how acquired DDR dysfunctions or pharmacological agents that block this pathway can be effectively exploited for the treatment of various hematopoietic malignancies.