Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions

Werner, Benjamin; Beier, Fabian; Hummel, Sebastian; Balabanov, Stefan; Lassay, Lisa; Orlikowsky, Thorsten; Dingli, David; Brümmendorf, Tim H.; Traulsen, Arne

doi:10.7554/elife.08687

Cited by 88 publications

(116 citation statements)

References 60 publications

(89 reference statements)

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“…In these differentiated cell types this shortening also continues during physiologic aging, but is much less pronounced. This suggests that telomere attrition may occur in human hematopoietic progenitor cells, given the shortening was seen in all cells examined in the bone marrow (57). Recently, non-critical shortening of telomeres has been shown to affect the expression of genes several Mb away through a process of chromosomal looping (58).…”

Section: Dna Damage In Hscsmentioning

confidence: 98%

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Beerman

2017

Seminars in Hematology

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Aging is associated with loss of functional potential of multiple tissue systems, and there has been significant interest in understanding how tissue specific cells contribute to this decline. DNA damage accumulation has been widely associated with aging in differentiated cell types. However, tissue specific stem cells were once thought to be a geno-protected population, as damage accrued in a stem cell population has the potential to be inherited by differentiated progeny as well as propagated within the stem cell compartment through self-renewal divisions. This review will discuss the evidence for DNA damage accumulation in the aged HSC compartment, potential drivers, and finally the consequences of the acquired damage.

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Section: Dna Damage In Hscsmentioning

confidence: 98%

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Beerman

2017

Seminars in Hematology

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“…20,21 Flow-FISH Vital sterile frozen MNC from PB was used for the flow-FISH analysis of TL, as previously described. [22][23][24][25][26] Briefly, samples were prepared for cell denaturation and mixed with an FITC-labeled telomere-specific (CCCTAA)3-peptide nucleic acid FISH probe (Eurogentec, Liège, Belgium) for DNA hybridization followed by DNA counterstaining with LDS 751 (Sigma). Bovine thymocytes were used as internal controls.…”

Section: Patientsmentioning

confidence: 99%

Comparison of flow‐FISH and MM–qPCR telomere length assessment techniques for the screening of telomeropathies

Ferreira

Kirschner

Halfmeyer

et al. 2019

Annals of the New York Academy of Sciences

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Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r 2 = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.

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“…In addition, initiating cells might die at a rate d per cell division. Differentiated cells proliferate at a rate D , also die at a rate d per cell division and undergo a maximum of m cell doublings before they enter cell senescence, resembling a Hayflick limit (4,5). Under these assumptions, the system takes the form of a hierarchically ordered, coupled set of ordinary differential equations that count the influx and outflux of cells of each compartment…”

Section: Quick Guide To Assumptions and Equationsmentioning

confidence: 99%

The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories

et al. 2016

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Many tumors are hierarchically organized and driven by a sub-population of tumor initiating cells (TICs), or cancer stem cells. TICs are uniquely capable of recapitulating the tumor and are implied to be highly resistant to radio- and chemotherapy. Macroscopic patterns of tumor expansion before treatment and tumor regression during treatment are tied to the dynamics of TICs. Until now, quantitative information about the fraction of TICs from macroscopic tumor burden trajectories could not be inferred. In this study, we generated a quantitative method based on a mathematical model that describes hierarchically organized tumor dynamics and patient-derived tumor burden information. The method identifies two characteristic equilibrium TIC regimes during expansion and regression. We show that tumor expansion and regression curves can be leveraged to infer estimates of the TIC fraction in individual patients at detection and after continued therapy. Furthermore, our method is parameter-free; it solely requires knowledge of a patient’s tumor burden over multiple time points to reveal microscopic properties of the malignancy. We demonstrate proof of concept in the case of chronic myeloid leukemia (CML), wherein our model recapitulated the clinical history of the disease in two independent patient cohorts. Based on patient-specific treatment responses in CML, we predict that after one year of targeted treatment, the fraction of TICs increases 100-fold and continues to increase up to 1000-fold after five years of treatment. Our novel framework may significantly influence the implementation of personalized treatment strategies and has the potential for rapid translation into the clinic.

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Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions

Cited by 88 publications

References 60 publications

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

Comparison of flow‐FISH and MM–qPCR telomere length assessment techniques for the screening of telomeropathies

The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories

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