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P.S. Godavarthy et al.
selectin in promoting HSC proliferation has been described.5 This could be explained by our previous work demonstrating that interactions with the BM microenvi- ronment differ drastically between normal HSC8 and LSC and even between oncogenes.15 However, in their study, Winkler et al. used GMI-1070, a pan-selectin antagonist and precursor to GMI-1271.5 In addition, a role for SCL/TAL1 in impeding the transition of HSC from G0 to G1 has been demonstrated,36 which may support the pro- proliferative effects of E-selectin on normal HSC.5 Additionally, similar to our findings, CD44 inhibited cell cycle progression of vascular smooth muscle cells in response to binding of high molecular weight hyaluro- nan,37 another CD44 ligand in the extracellular matrix, and modulated the ERK and AKT pathways upon cell adhesion via CD44.38 In the present study, it cannot be excluded that the SCL/TAL1-mediated reduction of CD44 expression may also have led to decreased binding to hyaluronan and osteopontin, another extracellular matrix protein known to bind CD44.39 However, CML induction did not differ significantly between wildtype and osteopontin-knockout mice (unpublished data, DSK), suggesting that, unlike E-selectin, osteopontin is not essential for the engraftment of LIC in CML.
In agreement with our work it was demonstrated that inhibition of E- and P-selectin led to reduced rolling of neutrophils on endothelium, lowering the risk of neu- trophil-mediated endothelial injury after xenotransplanta- tion.40 Furthermore, in CML, we previously showed that deficiency of E-selectin in BM endothelium or deficiency of L-selectin, P-selectin glycoprotein ligand (PSGL)-1, enzymes involved in the synthesis of selectin ligands6 or CD448 on LIC were required for efficient engraftment of LIC, whereas P-selectin in the BM was not required.6 Therefore, emphasis in this work was laid on E-selectin and its ligands. Treatment with GMI-1271 also reverted the insensitivity of multiple myeloma cells overexpressing
E-selectin ligands to bortezomib.12
Normal hematopoietic cells predominantly express the
standard isoform of CD44 (CD44s).41 However, variant isoforms of CD44 (CD44v) are generated in cancers, inclu- ding solid tumors42 and acute myeloid leukemia,43 but both forms, CD44s and CD44v, are cancer stem cell markers and both influence cancer cell stemness.42,44 In CML we found that the CD44s isoform has a role in homing and engraftment of LIC,8 while CD44v3 enhanced the repla- ting capacity of CML progenitors.45
In summary, regulation of CD44 expression via SCL/TAL1, the AKT pathway and an oncogene, as well as the mechanism of cell cycle regulation of LSC upon non- adhesion to the niche, suggest a concept of how disloca- tion from the niche may alter LSC proliferation and response to therapy. This has, similarly, been hypothe- sized in the case of the concomitant use of granulocyte colony-stimulating factor46,47 or C-X-C motif chemokine receptor (CXCR) 4 inhibitors plus tyrosine kinase inhibitors or chemotherapy in leukemia,48 suggesting that these therapeutic strategies may be further exploitable in the future.
Acknowledgments
The authors thank M. Zörnig for helpful discussions and Glycomimetics Inc., in particular J. Magnani and W. Fogler, for provision of drugs and initial funding of this work. The authors also thank Stefanie Dimmeler for use of the in vivo microscope. This work was supported by the LOEWE Center for Cell and Gene Therapy Frankfurt (CGT) and institutional funds of the Georg-Speyer-Haus to DSK. The Georg-Speyer-Haus is funded jointly by the German Federal Ministry of Health (BMG) and the Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK). The LOEWE Center for Cell and Gene Therapy Frankfurt is funded by HMWK, reference num- ber: III L 4-518/17.004 (2010). The project was also partly sup- ported by Deutsche Krebshilfe (SyTASC / 70111969).
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