The telomeric puzzle in TP53-mutant myeloid neoplasms Free

In this issue of Blood, Guarnera et al¹ report that telomere content (TC) in specific myeloid neoplasm subgroups (particularly those with complex karyotype and biallelic TP53 mutations) is unexpectedly similar to that in nonmalignant controls, whereas overall myeloid neoplasms generally have lower TC.

Telomeres are specialized DNA-protein structures at the ends of linear chromosomes. They consist of repetitive 6-nucleotide DNA sequences (TTAGGG in humans)² and are protected by a group of proteins called the shelterin complex.³ These proteins prevent the natural chromosome ends from being mistaken for DNA breaks and inhibit inappropriate repair attempts. Human telomere length (TL) typically ranges from 10 to 15 kb and gradually shortens with aging and during neoplastic transformation.⁴ Excessively short TL, a characteristic of telomere biology disorders caused by germ line defects in the telomerase components or associated telomere maintenance pathway contributors, not only leads to organ deficiencies such as cytopenias due to bone marrow failure but also increases the risk of developing myeloid neoplasm.

Guarnera et al performed whole-genome sequencing (WGS) on a large cohort (n = 1804) of patients with myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and myeloproliferative neoplasms (MPN). Nonmalignant controls (n = 158) included patients with clonal diseases (aplastic anemia and paroxysmal nocturnal hemoglobinuria), nonclonal cases (persistent polyclonal B-cell lymphocytosis), and healthy controls. Using an in silico tool, TelomereHunter, to estimate TC from WGS data, the authors reported that myeloid neoplasms generally have lower TC, particularly in cases of AML with t(8;21), FLT3 internal tandem duplication, and mutations in NPM1, KRAS, and NRAS.¹ This aligns with the expectation of a shorter TL due to increased replicative stress.

However, TC in specific adverse risk subgroups was unexpectedly similar to nonmalignant controls and higher than in those without the adverse risk features. In particular, biallelic TP53–mutated myeloid neoplasm samples showed significantly higher TC compared to wild-type or cases deemed likely to be monoallelic.¹ These findings align with a recent WGS study of TP53-mutated MDS/AML⁵ but contrast with earlier flow cytometry–based fluorescence in situ hybridization analysis reporting shorter TL in AML cases with copy number abnormalities and complex karyotypes.⁶ It is important to recognize that Guarnera et al measured total telomeric content (TC) in bulk DNA as an indirect indicator of TL—defined as the physical length of telomeric DNA at chromosome ends (see figure)—leaving actual TL in these cases undetermined.

Two established mechanisms maintain TL in cancer: telomerase—which is active in malignancies but largely inactive in normal somatic tissues—and the telomerase-independent alternative lengthening of telomeres (ALT) pathway, which functions in a subset of tumors.^7,8 Using the C-circle assay, Guarnera et al excluded ALT activity in their cohort. The authors then demonstrated that myeloid neoplasms with relatively higher TC exhibit increased expression of key telomeric maintenance genes such as TERC, suggesting that heightened telomerase activity drives the rise in TC.¹ 

Several possible reasons might explain an increase in TC without a corresponding increase in TL, or even despite a reduction in TL. Insertion of telomere-like sequences within chromosomes has been reported in about one-third of TP53-mutant MDS/AML cases,⁵ but was not evaluated in the current study. Additionally, de novo formation of telomeres (neotelomeres) at double-strand break sites, typically mediated by telomerase to repair and stabilize chromosome breaks, may contribute to increased TC; however, identifying such events requires long-read WGS.⁹ 

In this study, Guarnera et al highlight the complexity of telomere biology in myeloid neoplasms. Although the authors suggest that higher “telomeric reserve” from increased TC could confer resistance to telomerase inhibition,¹ this warrants further correlative studies, as it remains possible that dependence on telomerase-driven TC maintenance might render patients more susceptible to such therapies. The telomerase inhibitor imetelstat has shown promising clinical results in MDS and MPN,¹⁰ and future studies should endeavor to stratify patients based on combined measures of TL, TC, telomerase activity, and ALT pathway activity to better identify those who will benefit most from telomerase inhibitors.

Conflict-of-interest disclosure: I.S.T. received honoraria from Bristol Myers Squibb, Jazz Pharmaceuticals, and Pfizer. L.C.F. declares no competing financial interests.