Distinct Nuclear Organization of Telomeres and Centromeres in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Yu, Pak Lok Ivan; Wang, Rachel R.; Johnston, Grace; Wang, Yaqiong; Tammur, Pille; Tamm, Anu; Punab, Mari; Rangel‐Pozzo, Aline; Mai, Sabine

doi:10.3390/cells8070723

Cited by 4 publications

(11 citation statements)

References 46 publications

(67 reference statements)

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“…MM was the only group that displayed lytic lesions, as well as a greatly elevated level of serum M-protein compared to MGUS and SMM patients [ 5 ]. The most common immunoglobulin isotype in MM patients was IgG, followed by IgA, as previously described [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

“…Three-dimensional telomere profiles were measured using TeloView ® [ 21 ], which was used to assess the levels of telomere-related genomic instability and specific 3D telomere parameters associated with disease stability vs. progression [ 18 , 22 , 23 , 24 , 25 , 26 ]. To assess the potential of 3D telomere architecture as a reliable tool to differentiate MM from its precursor stages, we evaluated a total of 214 patients (54 MGUS, 24 SMM, and 136 MM).…”

Section: Resultsmentioning

confidence: 99%

“…Bone marrow samples were processed as previously described [ 18 ]. The white blood cells were isolated using Ficoll-Paque (GE Healthcare Life Sciences, Baie d’Urfe, QC, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…The malignant plasma cells were differentiated from normal lymphocytes based on their positive double staining for the MM markers CD138 and CD56, augmented nuclear size, and weaker DAPI counterstain, as it has been shown that malignant plasma cells show larger and weaker DAPI-stained nuclei than normal lymphocytes [ 18 , 19 ].…”

Section: Methodsmentioning

confidence: 99%

“…Irrespective of telomere length, the impaired/non-existent shelterin binding leads to “uncapped” telomeres that activate the DNA damage response, chromosomal fusion, and anaphase-bridging, leading in turn to breakage–bridge–fusion cycles and dynamic genomic instability with clonal evolution [ 16 , 17 ]. Telomere dysfunction is one of the mechanisms that may lead to the genetic and clinical heterogeneity observed in MM [ 16 , 18 , 19 ] and could therefore be of prognostic significance. Here, we compared different 3D telomere parameters from bone marrow samples across MGUS, SMM, and MM patients, prior to treatment, and investigated a potential prognostic role of telomere assessment in the spectrum of myeloma at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Rangel‐Pozzo

Lal

et al. 2021

Cancers

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Bone marrow samples were processed as previously described [ 18 ]. The white blood cells were isolated using Ficoll-Paque (GE Healthcare Life Sciences, Baie d’Urfe, QC, Canada).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Rangel‐Pozzo

Lal

et al. 2021

Cancers

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Three‐dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma

Kumar,

Rajkumar,

Jevremovic

et al. 2024

American J Hematol

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Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high‐risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high‐risk SMM patients remains an important clinical need. In this study, we present the 3‐dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20‐2‐20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20‐2‐20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

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3D nuclear architecture distinguishes thyroid neoplastic histotypes

Pozzo

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Molecular markers can be diagnostic tools to support pathological analysis in thyroid neoplasms. However, because the same markers can be observed in some benign thyroid lesions, additional approaches are necessary to differentiate thyroid tumour subtypes, prevent overtreatment and tailor specific clinical management. This applies particularly to the recently described variant of thyroid cancer referred to as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This variant has an estimated prevalence of 4.4% to 9.1% of all papillary thyroid carcinomas worldwide. We studied 60 thyroid lesions: 20 classical papillary thyroid carcinoma (CPTC), 20 follicular variants of PTC (FVPTC) and 20 NIFTP. We examined morphological and molecular features to identify parameters that can differentiate NIFTP from the other PTC subtypes.When blindly investigating the nuclear architecture of thyroid neoplasms, we observed that NIFTP has significantly longer telomeres than CPTC and FVPTC. Super-resolved 3Dstructured illumination microscopy demonstrated that NIFTP is heterogeneous and that its nuclei contain more densely packed DNA and smaller interchromatin spaces than CPTC and FVPTC, a pattern that resembles normal thyroid tissue. These data are consistent with the observed indolent biological behaviour and favourable prognosis associated with NIFTP, which lacks BRAF V600E mutations. Of note, next-generation thyroid oncological panel sequencing could not distinguish the thyroid cancer histotypes in our study cohort. In summary, our data suggest that 3D nuclear architecture can be a powerful analytical tool to diagnose and guide the clinical management of NIFTP.

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Distinct Nuclear Organization of Telomeres and Centromeres in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Cited by 4 publications

References 46 publications

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Three‐dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma

3D nuclear architecture distinguishes thyroid neoplastic histotypes

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