Three-dimensional Telomere Signatures of Hodgkin- and Reed-Sternberg Cells at Diagnosis Identify Patients with Poor Response to Conventional Chemotherapy

Abstract

In classic Hodgkin lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear Reed-Sternberg (RS) cells are characterized by a distinct three-dimensional nuclear telomere organization with shortening of the telomere length and the formation of telomeric aggregates. We asked if the severity of these telomere changes correlates with the clinical behavior of the disease. We retrospectively evaluated three-dimensional telomere organization by quantitative fluorescent in situ hybridization (Q-FISH) of diagnostic biopsies from 16 patients who were good responders and compared them with 16 diagnostic biopsies of 10 patients with refractory or relapsing HL (eight initial biopsies, four confirming progressions, and four confirming relapses). The H cells from patients with refractory/relapsing disease contained a significantly higher percentage of very small telomeres (P = .027) and telomere aggregates (P = .032) compared with H cells of patients entering rapid remission. These differences were even more significant (P = .002 and P = .013, respectively) when comparing the eight initial diagnostic biopsies of refractory/relapsing HL with diagnostic biopsies of eight patients with ongoing long-lasting remission (mean of 47 months). This specific three-dimensional telomere Q-FISH signature identifies these highly aggressive mononuclear H cells at the first diagnostic biopsy and thus may offer a new molecular marker to optimize initial treatment.

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

“…These telomere changes were absent in heterozygous Thrb PV/ + or control mice. Our findings confirm previous reports identifying 3D telomere FISH as an effective diagnostic tool for early detection of individual cancer cells, tumor subtypes, and suitable prognostic indicator of disease progression (24,25,31,62). Recently, we developed an automated 3D telomere scanning procedure capable of rapid imaging of telomere profiles from interphase nuclei, and specific TeloScan software was shown to identify individual tumor cells in large samples (63).…”

“…These events will ultimately lead to the generation of complex nonreciprocal translocations, a hallmark of solid tumours and genomic instability in general (20)(21)(22)(23). We previously showed significant differences in telomeric profiles (i.e., in telomere signal intensity and number, the presence/absence of telomeric aggregates, and in the number of telomeres per nuclear volumes) in therapy-sensitive and therapy-resistant Hodgkin's lymphoma patients (24). These results demonstrated the prognostic value of three-dimensional (3D) telomere diagnostic imaging for glioblastoma patients (25), and suggested a 3D telomere dysfunction-based progression model leading to the progression of myelodysplastic syndromes to acute myeloid leukemias (26).…”

Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

“…Two specific 3D telomere FISH patterns (established on 3D nuclear analysis of 30 H-cells and 30 RS-cells in each case) emerged at diagnosis [23]. The first pattern is associated with rapid and long lasting remission and is characterized by a rather low number (<40%) of very small telomeres (up to 5,000 U) in the mononuclear H-cells, the RS-cells generally displaying a high number (>60%) of very small telomeres.…”

“…All but 3 patients (two children, one adult with preexisting pulmonary disease) had identical first line ABVD chemotherapy. When compared to H-cells of patients entering rapid remission, H-cells of patients with progressing/relapsing disease showed significantly more very small telomere (65.6 ± 10.2% versus 39.9 ± 15.6%, p < 0.01) and aggregates (2.50 ± 0.87 versus 1.85 ± 1.16, p < 0.02) as well as a decrease of mean telomere intensity (definitions of these parameters according to [23]). Detailed clinical information about these two groups of patients is given in Table 1, Table 2.…”

LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates

“…17 Our recent observations document that very short telomeres are a hallmark of LMP1-expressing RS cells, even in young patients. 18 Short-term cultures of ex vivo EBV-infected normal human B lymphocytes show partial displacement of the telomeric protein TRF2, which is associated with a high level of nonclonal structural aberrations, namely Robertsonian translocations, unbalanced translocations, and chromatid gaps. 19 Furthermore, the EBV nuclear V.L.…”