Duncan Baird Cardiff University Translating telomeres - prognostic and predictive markers for cancer patients Duncan Baird Cardiff University

Telomere biology Telomeres shorten with ongoing cell division Short telomeres trigger a G1/S cell- cycle arrest (replicative senescence) Telomere length defines the replicative capacity of human cells Following the loss of a functional G1/S cell-cycle arrest telomeres continue to shorten Ultimately leading to complete loss of function and telomere fusion (crisis) Ensuing genome instability drives disease progression Baird. Exp. Rev. Mol. Med 2010

Replicative erosion Telomere erosion with ongoing cell division Fibroblast MRC-5 Gradual telomere erosion - 60-70 bp/PD Telomere length predicts replicative capacity PD=population doubling Baird et al. Nature Genetics 2003; Jones et al. Cell Reports 2014

Telomeres in CLL CLL B-cells clones - homogenous — clonal growth Short telomeres even prior to clinical progression Lin et al. Blood 2010

Defining the fusogenic threshold in CLL Thresholds used to stratify patient cohorts Lin. et al. B J Haem. 2014; Patent publication No: 2744913

Prognostics - CLL Telomere fusion threshold defines prognosis in CLL Telomere length is the strongest predictor of survival in CLL IGHV mutation CD38 Lin. et al. B J Haem. 2014

Response to CIT “Gold standard” treatment: fludarabine/cyclophosphamide/rituximab (FCR) Norris. et al. Leukemia. 2019; Patent publication No: 2744913 Figure 4. Kaplan Meier curves showing the ability of (A) IGHV mutation status, (B) CD38 expression and (C) B2M to predict overall survival following treatment with FCR.

Multiple Myeloma Hyatt et al. B J Haem 2017

Prognostics - Myeloma Telomere length is a critical determinant for survival in multiple myeloma Unsorted MM bone marrow samples Long telomeres Short telomeres Hyatt. et al. B J Haem. 2017; About to analyse a large MM clinical trial cohort of CD138+ sorted samples in collaboration with Mayo and Myeloma Foundation Hyatt et al. B J Haem 2017

Other tumour types Prognostic in MDS but not AML Myelodysplasia AML Splits high-risk subsets in Breast cancer and associates with genomic complexity Norris et al. In prep; Williams. et al. B. J. Haem. 2017;

Acknowledgments Telomere lab- Cardiff: Kez Cleal Collaborators: Julia Grimstead Rhiannon Jones Kate Liddiard Greg Ngo Kevin Norris Helene Geiller Alys Evans Laura Escudero Sam Hyatt Ceri Jones Thet Thet Lin Laureline Roger Jenna Williams Kate Simpson Nicole Heppel Bethan Britt-Compton Collaborators: Chris Pepper – Cardiff/Sussex Chris Fegan – Cardiff Guy Pratt – Birmingham Statistics: Robert Hills