Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway.

Abstract

Simple SummaryThe alternative lengthening of telomeres is a telomere maintenance mechanism used by some cancer types to elongate their telomeres without the aid of telomerase. This mechanism contributes to the proliferation and immortality of cancer cells. One of the hallmarks of this mechanism is the interaction with promyelocytic leukemia nuclear bodies, which are suspected to be the key places where telomere extension occurs. Despite the discovery of some mechanisms, elements, key genes, and proteins from the pathway, the alternative lengthening of telomeres mechanism is still poorly understood, and it is highly associated with a poor prognosis. In this study, we combined multiomics approaches with genomic, transcriptomic, and proteomic analyses of 71 genes/proteins related to promyelocytic leukemia nuclear bodies in more than 10,000 cancer samples from The Cancer Genome Atlas Consortium. As a result, 13 key proteins were proposed as candidates for future experimental studies that will validate these proteins as therapeutic markers, which will improve the understanding and treatment of these type of cancers. Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 Pan-Cancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT-positive cancers in the future.