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

Matheus Fabiao de Lima; Monique Oliveira Freitas; Mohammad K Hamedani; Aline Rangel-Pozzo; Xu-Dong Zhu; Sabine Mai

doi:10.3390/biomedicines10092299

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

Biomedicines. 2022 Sep 16;10(9):2299. doi: 10.3390/biomedicines10092299.

Authors

Matheus Fabiao de Lima¹, Monique Oliveira Freitas², Mohammad K Hamedani¹, Aline Rangel-Pozzo¹, Xu-Dong Zhu³, Sabine Mai¹

Affiliations

¹ Department of Physiology and Pathophysiology, CancerCare Manitoba Research Institute, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
² Genetic Service, Institute of Paediatrics and Puericulture Martagão Gesteira (IPPMG), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-912, Brazil.
³ Department of Biology, Faculty of Science, McMaster University, Hamilton, ON L8S 4K1, Canada.

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.

Keywords: BIBR 1532; alternative lengthening of telomeres (ALT); promyelocytic leukemia bodies (PML); telomerase; telomeric repeat-binding factor 1 (TRF1); trabectedin.

Grants and funding

The authors thank the Canadian Institutes of Health Research (CIHR) for CRC Tier 1 funding (S.M.), the Leukemia and Lymphoma Society of Canada (LLSC) for grant funding (S.M.), and Research Manitoba for funding support (M.F.d.L.).