Journal
CURRENT CANCER DRUG TARGETS
Volume 19, Issue 6, Pages 479-494Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568009618666180905100608
Keywords
Hematopoietic stem cells; mesenchymal stem cells; small molecules; bone marrow; c-myc; homology-directed repair
Categories
Funding
- European Commission
- Scientific and Technological Research Council of Turkey (TUBITAK) [115C039]
- TUBITAK ARDEB 1001 [115S185, 215Z069]
- TUBITAK ARDEB 3501 [215Z071]
- Science Academy Young Scientist Award Program (BAGEP2015, Turkey)
- International Centre for Genetic Engineering and Biotechnology - ICGEB [CRP/TUR15-02_EC]
- Medicine for Malaria Venture MMV Pathogenbox Award (Bill and Melinda Gates Foundation)
- Yeditepe University, Istanbul, Turkey
- TUBITAK-BIDEB 2211 program
- TUBITAK-BIDEB 2213 program
- Marie Curie Action COFUND of the 7th. Framework Programme (FP7)
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Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Methods and Results: Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34(low) HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclin-dependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-05 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL, improves HDR related gene expression. Conclusion: These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.
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