Page 12 - Read Online

Page 8 of 17 Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111

Importantly, E-selectin expression was observed at the level of bone marrow areas where leukemia cells
[42]
home at the moment of their engraftment . Xenograft models of immune-deficient mice transplanted
+
with AML blasts showed that a small number of CD34 leukemic stem cells that survived antileukemia
chemotherapy was detected under form of clusters located around endosteal vascular endothelium, a
region where E-selectin is expressed on endothelial cells [43,44] .

Recent studies have shown a direct role of bone marrow vascular E-selectin expression in homing and
chemoresistance of leukemic cells. Thus, Winkler et al. initially reported a remarkable up-modulation
[45]
of E-selectin expression on the bone marrow vasculature in mice with AML; studies in the murine AML
model generated by retroviral transduction of the MLL-AF9 fusion oncogene into HSCs showed that
leukemic blasts rapidly upregulate E-selectin expression following oncogenic transformation. Experiments
based on genetic or pharmacological inhibition of E-selectin expression provided evidence that E-selectin
expression is important for retention of leukemic stem cells in bone marrow and protects leukemic stem
cells from the cytotoxic effects of chemotherapy . In a more recent study, the same authors showed that
[45]
[46]
MLL-AF9 AML cells surviving cytarabine therapy display an increased E-selectin binding potential . This
is due to the capacity of these leukemic cells to interact with E-selectin-positive endothelial cells present in
the vascular niche. This conclusion is supported by two lines of observations: (1) vascular niche E-selectin
blockade by GMI-1271, a specific inhibitor of E-selectin binding, inhibits malignant AML reconstitution/
survival potential in vivo; and (2) these effects occur through the inhibition of several pro-survival signals
induced in leukemic cells . According to these observations, it was suggested that E-selectin blockade
[46]
[46]
may synergize with other pathway inhibitors to improve the therapeutic response of AML patients .
In a more recent study, the same investigators showed that AML cells generate an inflammatory state in
the bone marrow at the level of the sites where they home, driving increased E-selectin expression on bone
[47]
marrow endothelial cells [Figure 2]. This condition creates the basis for the interaction between leukemic
cells and E-selectin-expressing endothelial cells, triggering the generation of pro-survival signaling
(PI3K/AKT and mTOR pathways) that stimulates leukemic cell proliferation and promotes leukemic
[47]
chemoresistance . These observations support the clinical use of E-selectin inhibitors in combination
with standard induction chemotherapy for AML patients. The preliminary results of a phase I clinical
trial involving the administration of GMI-1271 in combination with induction chemotherapy to a group
of 19 relapsed/refractory AML patients showed a high response rate (42% of complete responses), with
a sufficient duration of response to allow five patients to proceed to salvage stem cell transplant. Phase II
of this study is ongoing and implies two arms of treatment, one corresponding to an expansion cohort of
phase I and the other involving treatment of newly diagnosed AML patients ≥ 60 years.

Very recently, the membrane E-selectin receptor expressed on HSCs and responsible for induction of
[48]
chemoresistance was identified . E-selectin may interact with two different membrane receptors, CD44
and CD162, expressed on hematopoietic cells. To explore this issue, Erbani and coworkers used the
+
CD34 human myeloid cell line KG1a. This cell line express CD44 and CD162, and both of these receptors
are functional in terms of E-selectin binding capacity. Only the silencing of both receptors abrogates
the capacity of KG1a cells to bind E-selectin; however, only CD162 is critical for E-selectin-mediated
chemoresistance in vitro. Importantly, CD162 expression on AML cells in vivo is a major determinant for
[48]
E-selectin binding, bone marrow vascular niche retention, and leukemic progression [Figure 2]. Deletion
[48]
of CD162 in AML cells induces a clear increase of the sensitivity of leukemia stem cells to therapy .
According to these findings, it was suggested that the binding of CD162 to E-selectin represents a potential
therapeutic target to improve therapeutic outcomes through a potentiation of the efficacy of antileukemic
chemotherapy.

Interestingly, recent studies carried out on chronic myeloid leukemia (CML) led to evidence similar to
that observed in AML about a key role of interactions with E-selectin mediating leukemic homing and