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

2. 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

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

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

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

6. 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

7. Response to CIT
“Gold standard” treatment: fludarabine/cyclophosphamide/rituximab (FCR)
Norris. et al. Leukemia. 2019; Patent publication No:
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.

8. Multiple Myeloma
Hyatt et al. B J Haem 2017

9. 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

10. 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;

11. 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