The Molecular Mechanisms and Therapeutic Prospects of Alternative Lengthening of Telomeres (ALT)

Abstract

As detailed by the end replication problem, the linear ends of a cell’s chromosomes, known as telomeres, shorten with each successive round of replication until a cell enters into a state of growth arrest referred to as senescence. To maintain their immortal proliferation capacity, cancer cells must employ a telomere maintenance mechanism, such as telomerase activation or the Alternative Lengthening of Telomeres pathway (ALT). With only 10–15% of cancers utilizing the ALT mechanism, progress towards understanding its molecular components and associated hallmarks has only recently been made. This review analyzes the advances towards understanding the ALT pathway by: (1) detailing the mechanisms associated with engaging the ALT pathway as well as (2) identifying potential therapeutic targets of ALT that may lead to novel cancer therapeutic treatments. Collectively, these studies indicate that the ALT molecular mechanisms involve at least two distinct pathways induced by replication stress and damage at telomeres. We suggest exploiting tumor dependency on ALT is a promising field of study because it suggests new approaches to ALT-specific therapies for cancers with poorer prognosis. While substantial progress has been made in the ALT research field, additional progress will be required to realize these advances into clinical practices to treat ALT cancers and improve patient prognoses.

Sarcoma_CellminerCDB: A tool to interrogate the genomic and functional characteristics of a comprehensive collection of sarcoma cell lines

“… 42 TERT negative cancer cells use an alternative pathway called the alternative lengthening of telomeres (ALT) pathway which is active in about 10–15% of cancers, especially in osteosarcomas, and may have therapeutic implications. 45 , 46 , 47 , 48 Using Sarcoma_CellMinerCDB, we analyzed osteosarcoma cell lines for TERT mutations and expression. Among the 59 sarcoma cell lines sequenced in the NCI database, the 27 cell lines of the GDSC and the 30 cell lines of the CCLE, deleterious TERT mutations were only found in one cell line sequenced at the NCI: the CHLA-59 osteosarcoma cell line.…”

Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

“…Aside from our in vitro experiments, we extended our investigation to demonstrate that arsenic trioxide also disrupts APBs and ssTeloC in mouse xenografts. Although multiple compounds have been investigated for ALT targeting, these studies have predominantly been conducted in cultured cells, serving primarily as proof of concept ( 44 , 67 ). Nevertheless, our study demonstrates for the first time that a clinically approved drug can inhibit features of ALT activity in vivo .…”

Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma

“…The low prevalence of ALT in histiocytic sarcoma is surprising. In general, about 10-15% of tumors use ALT as their maintenance mechanism, but some tumors like mesenchymal tumors tend to show high ALT activity in both humans and canines [6,12,36]. For example, osteosarcomas show a prevalence over 60% in humans and a prevalence of 20% in canines.…”

“…Telomerase is preferentially activated in most human and canine tumors [3,4]. However, ALT is used in about 10-15% of human cancers as a telomeraseindependent TMM based on homologous recombination [5,6]. The measurement of ALT activity has the potential to become a quantifiable tumor marker that is important for prognosis and diagnosis as well as for personalized therapy as TMM-specific therapeutics emerge [5][6][7].…”

“…However, ALT is used in about 10-15% of human cancers as a telomeraseindependent TMM based on homologous recombination [5,6]. The measurement of ALT activity has the potential to become a quantifiable tumor marker that is important for prognosis and diagnosis as well as for personalized therapy as TMM-specific therapeutics emerge [5][6][7]. In addition, the therapeutic inhibition of telomerase can lead to ALT as a resistance mechanism [8].…”