1. Investigating the bone marrow microenvironment in MGUS and multiple myeloma – evidence for early and irreversible transformation
Daniel A Tennant
Institute of Metabolism and Systems Research
University of Birmingham

2. Investigating a changing network through its metabolic footprint
Read-out of:
Cell number
Cell phenotype
Microenvironment
Cell-cell communication
Haas et al. TiBS (2016)

3. Metabolic transformation of the bone marrow is an early event in the aetiology of MM
Changes in the bone marrow phenotype are early
Ludwig et al. Blood Cancer J (2015)

4. Multiple complex changes across the bone marrow metabolic network
Ludwig et al. Blood Cancer J (2015)

5. This metabolic change can be observed in the peripheral blood
Observable change is significant, but small
Ludwig et al. Blood Cancer J (2015)

6. Enhanced urea – signs of early altered bone marrow function
Blair et al. Pract Neurol (2014)

7. BMMSCs are a critical stromal cell type supporting plasma cells
Hideshima and Anderson. Nature Rev Cancer (2002)

8. Gene expression signature of BMMSCs changes with disease onset
Ctrl
MGUS MM
Primary BMMSCs cultured for <5 passages
McNee et al. (2017) Leukemia

9. PADI2 expression is high in MGUS and MM bone marrow mesenchymal stem cells
Previously-described PADI2 target
Urea transporter
McNee et al. (2017) Leukemia

10. Peptidyl arginine deiminases
Family of 5 enzymes that deiminate peptidyl arginyl residues to form citrulline
Jang et al. J Bacteriol Virol (2013)

11. Action of the PADI enzymes

12. A significant increase in PADI2 expression is observed in BMMSCs from both MGUS and MM
McNee et al. (2017) Leukemia

13. PADI2 expression correlates with IL-6 expression in in vitro and in vivo
McNee et al. (2017) Leukemia

14. IL-6 expression is downstream of PADI2 catalytic activity
McNee et al. (2017) Leukemia

15. Citrullination of arginine 26 of histone H3 is increased in primary BMMSCs
McNee et al. (2017) Leukemia

16. PADI2 activity results in citrullination of the IL-6 promoter region
McNee et al. (2017) Leukemia

17. PADI2 modulates expression of multiple chemokines with a role in myeloma pathogenesis
McNee et al. (2017) Leukemia

18. PADI2 activity modulates therapy responsiveness of co-cultured myeloma cells
McNee et al. (2017) Leukemia

19. Early changes in BMMSC phenotype alter myeloma cell behaviour
How does PADI2 become upregulated in early disease?
McNee et al. (2017) Leukemia

20. Acknowledgements University of Birmingham Clare Davies Federica Cuozzo
Katherine Eales
Cristina Escribano
Kate Hollinshead
Gavin McNee
Haydn Munford
Katarina Kluckova
Alpesh Thakker
National NMR facility
Christian Ludwig
Clare Davies
Paul Moss
Sarah Essex
David Bartlett
Guy Pratt
Royal Wolverhampton Hospital
NHS Trust
Supratik Basu
Angelique Barkhuizen