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Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111 Page 7 of 17

Figure 2. Role of endothelial E-selectin in the control of HSC and LSC. (Left) under steady-state conditions, few bone marrow
endothelial cells express the adhesion molecule E-selectin on their surface, mediating in few instances the interaction with the CD44
receptor expressed on HSCs; (middle) under conditions of bone marrow regeneration following damage caused by radiotherapy or
chemotherapy, E-selectin expression on bone marrow endothelial cells markedly increases and promotes HSC proliferation; (right) in
AML patients, the inflammatory microenvironment promotes a marked increase of E-selectin expression on bone marrow endothelial
cells, mediating its interaction with the CD162 receptor overexpressed on the surface of LSCs. GMI-1271, a E-selectin inhibitor,
blocks the interaction between E-selectin and CD162, reducing the binding of LSCs to endothelium and their chemoresistance. HSC:
hematopoietic stem cell; LSC: leukemic stem cell

in bone marrow leukemic blasts and in bone marrow serum; AML patients exhibiting high levels of bone
[40]
marrow OPN showed a reduced overall survival . The prognostic role of OPN was particularly evident at
[40]
the level of the intermediate risk AMLs .
TARGETING LEUKEMIC ENDOTHELIUM
Another set of recent studies has shown the key role of some adhesion molecules expressed on endothelial
cells of the vascular niche in homing, survival, and chemoresistance of AML cells. E-selectin, also known
as ELAM-1 (endothelial-leukocyte adhesion molecule-1) or CD62E (CD62 antigen-like family member
E), is a selectin cell adhesion molecule selectively expressed on activated endothelial cells. E-selectin binds
to different ligands expressed on various types of hematopoietic cells. E-selectin mediates the adhesion of
some tumor cell types to endothelium through the interaction with ligands expressed on tumor cells.

E-selectin is constitutively expressed on bone marrow endothelium, where it plays a key role in allowing
the homing and engraftment of HSCs/HPCs that express the correspondent ligands. Winkler et al.
[41]
showed that an increase of E-selectin at the vascular HSC niche in the bone marrow corresponds to a
stimulation of proliferation and differentiation of dormant HSCs: following antileukemic chemotherapy or
radiation treatment, E-selectin expression increases at the level of bone marrow by about 10-20-fold during
the recovery phase of hematopoiesis in correspondence with the reparative proliferation and differentiation
of HSCs; a genetic or pharmacologic inactivation of E-selectin reduces this response and increases the
proportion of HSCs returning to quiescence [Figure 2]. Interestingly, deletion or blockade of E-selectin
significantly enhanced the survival of normal HSCs after treatment of mice with chemotherapeutic drugs
or irradiation . These effects do not seem to be mediated by canonical E-selectin ligands, such as CD44
[41]
[41]
and CD162 .