Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin’s Lymphoma Cell Death

Abstract

Telomere maintenance is key during cancer development. Malignant cells can either use telomerase or an alternative lengthening of telomere (ALT) pathway to maintain their telomere length. In Hodgkin’s Lymphoma (HL), the presence of telomerase activation is established. The activation of ALT has been reported recently. Our data confirm this notion describing co-localization of the phosphorylated form of telomeric repeat-binding factor 1 (pT371-TRF1) with ALT-associated promyelocytic leukemia bodies. Surprisingly, to our knowledge, there are no published studies targeting both telomere maintenance pathways in HL. Consequently, we investigated, for the first time, the effects of both telomerase and ALT inhibition on HL cell viability: We inhibited telomerase and/or ALT, given either individually, simultaneously, or consecutively. We report that the inhibition of telomerase using BIBR1532 followed by ALT inhibition, using trabectedin, caused a decrease of greater than 90% in cell viability in three patient-derived HL cell lines. Our results suggest that HL cells are most vulnerable to the consecutive inhibition of telomerase followed by ALT inhibition.

In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869

“…However, we found that bleomycin, which is part of ABVD treatment, the NF-kB inhibitor DHMEQ [29], and trabectedin had comparable activity in HRS and HRSdx cells [11]. Trabectedin, able to counteract HRS/TME interactions [53] and to enhance the anticancer activity of the inhibitor of telomerase activation BIBR153 in HRS cells [54], could be a promising option for patients with refractory/resistant cHL.…”

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

“…Telomere dysfunction in HODGKIN includes extremely short telomeres, altered telomere numbers, telomere aggregation, and changes in 3D spatial structure [ 39 ]. Furthermore, previous studies have shown that sequential inhibition of telomerase and ALT promotes the cell death in HODGKIN [ 40 ]. Our findings indicated that genetic variants associated with longer TL were associated with an increased risk of HODGKIN.…”

A novel telomere-related genes model for predicting prognosis and treatment responsiveness in diffuse large B-cell lymphoma

“…Among these two pathways, telomerase activation is more common and has been reported in almost all types of tumors [ 11 , 12 ]. In lymphoma, Lima et al reported that Hodgkin lymphoma (HL) cells are most likely to have telomerase activation pathways that extend telomeres, followed by the ALT pathway [ 13 ]. But there are no relevant reports in DLBCL.…”