Nuclear remodeling of telomeres in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a hematologic cancer characterized by the proliferation of myeloid cells and the translocation between chromosomes 9 and 22, [t(9;22)(q34.1;q11.2)]. At the chronic phase (CP), CML cells present longer telomeres than at the other clinical phases, display arm-specific maintenance of individual telomere lengths, and are chromosomally stable. We asked whether an alteration of nuclear organization of telomeres, which is associated with genomic instability, occurs in CML cells at the CP. We used fluorescent in situ hybridization of telomeres combined with three-dimensional (3D) quantification to study the nuclear telomeric architecture of CML cells at the CP. We found that cells can exhibit high telomere numbers, different telomere distributions, and alterations in peripheral or central nuclear location of telomeres. Also, we show that CML cells can be categorized in two groups according to the number of their telomere aggregates (TAs). We propose that the presence of high TAs in some samples is associated with the increased genomic instability and could be an indication of the clinical transitional phase. Also, alterations of nuclear organization of telomeres at the CP confirm that nuclear remodeling of telomeres can occur at an early clinical stage of a cancer.

Dynamic Length Changes of Telomeres and Their Nuclear Organization in Chronic Myeloid Leukemia

“…However, only two studies have explored telomeric nuclear organization in CML. The first study was done on twelve patients at their diagnosis (CP) and revealed an alteration of telomeric nuclear organization, marked by high number of telomeric aggregates (TAs) as well as changes in telomeric position [87]. This study clearly indicated that an alteration of telomeric nuclear organization could occur at an early clinical phase of a malignancy, as previously hypothesized [35].…”

“…The alteration of telomeric nuclear organization has been reported in many cancers [28,31,32,86,87]. However, only two studies have explored telomeric nuclear organization in CML.…”

“…Most notably, in this study, patients were categorized into two groups according to the number of TAs: patients with normal number of TAs and patients presenting four times normal level of TAs. However, this study failed to evaluate the clinical values of this high number of TAs because of lack of some clinical information [87]. Nevertheless, an increase number of TAs in CP might be a surrogate for therapeutic response, as shown in Hodgkin lymphoma [86] or might present prognostic values, as reported in glioblastoma [31].…”

“…Besides the presence of telomeric aggregates, it has been shown that telomeres in some CML cells can be either more centrally or peripherally located when they were compared to those of normal cells [87]. Differential positioning of telomeres in CML cells might be a consequence of nuclear remodeling.…”

Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres

“…5F). This peripheral location of telomeres has been associated with nuclear scaffold dysfunction (Gonzalez-Suarez et al, 2009) and found in some cancers such as chronic myeloid leukemia (Samassekou et al, 2013). Furthermore, the telomere displacement from central (wild type) to peripheral (mutants) nuclear location might be going along with nuclear remodeling of chromosomes that is associated with structural chromosome abnormalities (Louis et al, 2005).…”