Alternative Lengthening of Telomeres pathway (ALT)

The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent mechanism used by approximately 10-15% of human cancers to maintain telomere length and achieve cellular immortality (Dilley and Greenberg, 2015, Nat Struct Mol Biol). Unlike most cancers that upregulate telomerase, ALT-positive cells utilize a homology-directed repair (HDR) process to copy telomeric DNA from other telomeres or extrachromosomal DNA templates (Sobinoff and Pickett, 2017, JMB). This pathway is frequently associated with mutations in the chromatin remodeling proteins ATRX or DAXX and is characterized by high levels of telomeric replication stress and genomic instability (Heaphy et al., 2011, Science). Because ALT-positive cells are uniquely dependent on specific DNA damage response (DDR) proteins, such as ATR kinase, to manage this stress, these proteins have emerged as promising therapeutic targets (Flynn et al., 2015, Science). Current clinical strategies focus on using ATR inhibitors or PARP inhibitors to selectively induce synthetic lethality in ALT-positive tumors, which include specific subtypes of osteosarcoma, glioblastoma, and soft tissue sarcomas (Kim et al., 2019, JCI). Monitoring for ALT activity typically involves detecting C-circles or ALT-associated PML bodies (APBs) in patient samples to guide therapy (Henson et al., 2009, Nat Biotechnol).

Other names

ALT mechanismTelomerase-independent telomere maintenanceHomologous recombination-mediated telomere lengtheningALT telomere maintenance

Inhibition of the DNA damage response (DDR) proteins, particularly ATR kinase, which ALT-positive cells rely on to manage high levels of replication stress and telomeric DNA damage (Flynn et al., 2015, Science). Other strategies include G-quadruplex stabilization to induce telomeric instability or PARP inhibition to disrupt recombination-mediated repair and induce synthetic lethality (Kim et al., 2019, JCI).