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Editorials
blood vessels and activate E-selectin on the endothelium, allowing engraftment of immune progenitor cells. This ini- tial binding of E-selectin to its ligand confers firm adhesion, and triggers signaling that leads to permabilization of the endothelium through the dissociation of VE-cadherin/β- catenin. In an attempt to counteract metastasis, the E- selectin inhibitor GMI-1271 is currently being tested in pre- clinical models and is showing high efficacy.17 As well as being a therapeutic target, E-selectin is also being screened as a potential biomarker for disease progression and metas- tasis.19
The BM microenvironment is a developing research focus which is showing great importance in disease patho- physiology. Advances in technology, such as the time-lapse intra-vital imaging used in the study by Godavarthy et al.,1 are enabling a greater understanding of the interactions and mechanisms involved in cellular microenvironments This type of pioneering microscopy allows us to see interactions between leukemic cells and the niche, and is providing powerful data, as exemplified by this study as well as many others.13 Enriching these data, single-cell RNA-sequencing allows for the analysis of the different cell types within the niche, evaluation of their transcriptional regulation and a view of how they may contribute to disease progression, providing important information which may have been masked using bulk sequencing approaches.20 Through these studies, we continue to build upon our knowledge of the pathophysiology of CML and come ever closer to finding a way of eradicating quiescent LSC.
References
1. Godavarthy PS, Kumar R, Herkt SC, et al. The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E- selectin - SCL/TAL1 - CD44 axis . Haematologica. 2019;05(1):136-147.
2. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of ima- tinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-927.
3. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319-325.
4. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315-1321.
5. SchepersK,PietrasEM,ReynaudD,etal.Myeloproliferativeneoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell. 2013;13(3):285-299.
6. WelnerRS,AmabileG,BarariaD,etal.Treatmentofchronicmyeloge- nous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27(5):671-681.
7. Krause DS, Lawarides K, Lewis JB, von Andrian UH, Van Etten RA. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood. 2014;123(9):1361-1371.
8. MorrisonSJ,ScaddenDT.Thebonemarrownicheforhaematopoietic stem cells. Nature. 2014;505(7483):327-334.
9. PeledA,KolletO,PonomaryovT,etal.ThechemokineSDF-1activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000;95(11):3289-3296.
10. Frenette PS, Subbarao S, Marzo IB, von Andrian UH, Wagner DD. Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc Natl Acad Sci U S A. 1998;95(24):14423-14428.
11. Oostendorp RAJ, Ghaffari S, Eaves CJ. Kinetics of in vivo homing and recruitment into cycle of hematopoietic cells are organ-specific but CD44-independent. Bone Marrow Transplant. 2000;26(5):559-566.
12. ZhangB,HoYW,HuangQ,etal.Alteredmicroenvironmentalregula- tion of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012;21(4):577-592.
13. Bhatia R, Verfaillie CM. The effect of interferon-α on beta-1 integrin mediated adhesion and growth regulation in chronic myelogenous leukemia. Leuk Lymphoma. 1998;28(3-4):241-254.
14. Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells. Nat Med. 2006;12(10):1175-1180.
15. ErbaniJ,BarbierV,LoweJ,TayJ,LevesqueJP,WinklerI.Vascularniche E-selectin promotes acute myeloid leukemia resistance to chemothera- py via its receptors CD44 and CD162. Exp. Hematol. 2018;64:S63.
16. ChienS,HaqSU,PawlusM,etal.Adhesionofacutemyeloidleukemia blasts to E-selectin in the vascular niche enhances Their Survival By Mechanisms Such As Wnt Activation. Blood. 2013;122(21):61.
17. Kang SA, Blache CA, Bajana S, et al. The effect of soluble E-selectin on tumor progression and metastasis. BMC Cancer. 2016;16:331.
18. Köhler S, Ullrich S, Richter U, Schumacher U. E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung. Br J Cancer. 2010;102(3):602-609.
19. Aref S, Salama O, Al-Tonbary Y, Fouda M, Menessy A, El-Sherbiny M. L and E selectins in acute myeloid leukemia: expression, clinical rele- vance and relation to patient outcome. Hematology. 2002;7(2):83-87.
20. Tikhonova AN, Dolgalev I, Hu H, et al. The bone marrow microenvi- ronment at single-cell resolution. Nature. 2019;569(7755):222-228.
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