Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Abstract

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma

“…Facilitating these studies are recent efforts to use cell lines and patient cells to construct 3D organoids to reconstruct the bone marrow environment [121,122]. These systems are being used to study the pathogenesis of MM [123] and to develop new chemo-and immune therapies [124,125]. Given that MM remains an incurable disease, this information might allow a more rational assembly of induction therapy combinations that could be personalized and contribute to a more resilient anti-MM immune response and extended survival.…”

Next-Generation Biomarkers in Multiple Myeloma: Understanding the Molecular Basis for Potential Use in Diagnosis and Prognosis

“…A recent study by Aline et al compared, in a longitudinal prospective study, the 3D telomeric architecture including telomere intensity, numbers, aggregate and nuclear volume in BM samples from patients with MGUS, SMM or MM, with a minimum follow-up of 5 years. Interestingly, alterations of the telomere structure were specific to different phases of MM and correlated with the aggressiveness of the disease [ 95 ]. For instance, there was a substantial increase in telomere numbers in MGUS, when compared with MM.…”

“…For instance, there was a substantial increase in telomere numbers in MGUS, when compared with MM. Meanwhile, total telomere intensity and nuclear volume were significantly higher in SMM compared with both MGUS and MM [ 95 ]. Furthermore, the intensification of all or some of the above-mentioned telomere parameters was correlated with SMM with a high risk of progression and MM with progressive disease [ 95 ].…”

“…Meanwhile, total telomere intensity and nuclear volume were significantly higher in SMM compared with both MGUS and MM [ 95 ]. Furthermore, the intensification of all or some of the above-mentioned telomere parameters was correlated with SMM with a high risk of progression and MM with progressive disease [ 95 ]. Other studies have linked the risk, outcome, prognosis, disease heterogeneity, cytogenetic status and OS in MM cases with telomerase activity and telomere length [ 92 , 96 , 97 ], indicating the potential diagnostic and prognostic properties of telomere in MM.…”

Myeloma: A Lot of Progress, Still a Long Way to Go

“…Still, a better understanding of the molecular mechanisms of aggressive tumour biology may help to expose the Achilles’ heel of the disease. Certainly, the aberrant three-dimensional organization of the telomeres may be a marker of genomic instability and consequential disease aggressiveness, as described by Rangel-Pozzo and co-workers [ 1 ]. Short and dysfunctional telomeres with a reduced ability to bind protective shelterin proteins can lead to “uncapped” telomeres that activate the DNA damage response and may drive genomic instability, leading to aggressive tumour biology.…”