Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Abstract

Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34 þ 38À hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to diseasemodifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.

Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

“…Although stem cells should be able to repair their telomeres to secure their immortality, these cells are not spared from the aging process. Telomere studies in patients after BM transplantation demonstrate accelerated loss, resulting from a small stem cell reserve and high demand for cell production (42). In RA, 30-year-old patients had telomere sequences that were consistent with those in the 60-year-old healthy controls, suggesting profound differences in the HPC life cycle and replication.…”

A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish

“…However, DC patients usually die of bone marrow failure due to a deficient renewing capability of HSCs 8,9 . Curiously, the presentation of the disease is more serious in patients with mutations affecting TR 7 and some mutations, such as 58G-A, are not associated with impaired telomerase activity in vitro 35 .…”

“…DC patients show signs of premature aging and they are more susceptible to develop cancers. All DC patients have some defects in telomere biology and those defects affect the renewing capabilities of HSCs 8,9 . All mutations identified to date in DC patients are found in telomerase components or in telomere-stabilizing components 7 .…”

MART-1–Specific Melanoma Tumor-Infiltrating Lymphocytes Maintaining CD28 Expression Have Improved Survival and Expansion Capability Following Antigenic Restimulation In Vitro

“…We did not separately measure telomere length in the post-REP CD28 + and CD28 2 TILs using the flow-FISH assay because of the low numbers of CD28 + remaining in the cultures. However, after analyzing multiple TIL lines, the average telomere length in the CD8 + population following the REP was still 3.7 kb, a length still sufficient to support more cell division (36)(37)(38). In addition, we have tried a stronger T cell stimulus by activating post-REP TILs using plate-bound anti-CD3 Abs and IL-2.…”