1. CD38 drives mitochondrial trafficking promoting bio-energetic plasticity in multiple myeloma
Christopher R Marlein
PhD Student
Department of Molecular Haematology
University of East Anglia
Norwich, UK

2. ASH 2017 – Atlanta, GA

3. Oxidative phosphorylation (mitochondria)
Introduction
Glucose
Multiple myeloma (MM) relies on its micro-environment to proliferate and survive.
MM requires large amounts of energy to fuel numerous cellular processes including paraprotein production.
MM cell lines have been shown to rely on the “Warburg hypothesis”, whereby their ATP is generated through glycolysis.
The primary aim of this study was to examine the effect of BMSC on the metabolism of MM cells both in-vitro and in-vivo.
Pyruvate MM
Glycolysis
(cytoplasm)
Oxidative phosphorylation (mitochondria)
ATP
ATP

4. MM has increased growth capacity and ATP generation on BMSC

5. MM has increased OXPHOS on BMSC

6. MM has increased OXPHOS on BMSC

7. MM has increased OXPHOS in-vivo

8. Does mitochondrial transfer occur from BMSC to MM?
It has been shown that mitochondria can move from BMSC to both malignant and non-malignant cells (Marlein 2017, Moshoi 2016, Islam 2012)
Do MM harness the mitochondria from BMSC to aid OXPHOS?

9. Mitochondria are transferred from BMSC to MM cells
#1 MitoTracker staining and Flow Cytometry

10. Mitochondria are transferred from BMSC to MM cells
#2 In vivo xenograft NSG model

11. Mitochondria are transferred from BMSC to MM via TNT

13. Bio-energetic consequence of CD38 regulated mitochondrial transfer

14. CD38 silencing reduces mitochondrial transfer in-vivo

15. CD38 silencing reduces mitochondrial transfer in-vivo

16. Conclusions MM has increased levels of OXPHOS when grown with BMSC.
To increase OXPHOS mitochondria are transferred from the non-malignant BMSC to MM.
CD38 KD reduces mitochondrial transfer, through inhibition of TNT formation.
CD38 KD in vivo reduces mitochondrial mass in MM and improves animal survival.

17. Acknowledgements Patients and families University of East Anglia
Department of Molecular Haematology
Principal Investigators:
Dr Stuart Rushworth
Professor Kristian Bowles
Senior Research Associate:
Dr Lyubov Zaitseva
PhD Students:
Rachel Piddock
Dr Amina Abdul-Aziz
Dr Manar Shafat
Yu Sun
Academic Clinical Fellow:
Dr Charlotte Hellmich
Research Technicians:
Yvette Wormstone
Glenn Harden
MRes Students:
Adam Morfakis
Rebecca Horton
Eoghan Forde
Norfolk and Norwich University Hospital Myeloma Clinic
Consultant Haematologists
Dr Martin Auger Professor Kristian Bowles Dr Cesar Gomez