telomere

Alternative Lengthening of Telomeres (ALT)

Hallmarks of ALT are heterogeneity of telomere lengths, circular telomeric DNA, and the association between telomeres and the promyelocytic leukemia (PML) protein.

This protein was first discovered as the product of the PML gene, which fuses with the RARα gene in the t(15;17) chromosomal translocation. This chromosomal abnormality causes the human acute promyelocytic leukemia (APL), where a fusion PML/RARα protein is expressed.

In normal cells, the PML protein aggregates nuclear structures called PML nuclear bodies (PML-NBs), where it interacts with multiple protein partners to accomplish a wide variety of functions, including regulation of transcription and p53 activation.

PML also participates in DNA damage response and is overall regarded as a tumor suppressor. The interaction between the PML protein and telomeres is clearly recognized in ALT cells, where the PML protein is present within telomeric bodies named ALT-associated PML nuclear bodies.

However, the specific role played by the PML protein in this context is still under investigation. Another fundamental question is whether PML-NBs exert a telomeric function in normal cells. Evidence for the presence of the PML proteins at the telomeres of non-neoplastic cells have been reported in human endothelial cells and mouse embryonic stem cells, where the PML protein appears to be relevant for telomeres stability.

However, it is not clear whether this localization is functionally significant nor if it has a role upon proliferative telomeric attrition or damage. Another open question is whether an altered function of the telomeric PML could contribute to the pathogenesis of leukemia. The PML/RARα protein33 acts as a transcriptional repressor of RARα and non-RARα target genes and disrupts the PML-NBs exerting a dominant negative activity on their function. Whether the leukemogenic function of the PML/RARα protein involves an alteration of the function of PML at telomeres is still unknown.