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Editorials
Defining niche interactions to target chronic myeloid leukemia stem cells
Rebecca Mitchell and Mhairi Copland
Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK E-mail: MHAIRI COPLAND - mhairi.copland@glasgow.ac.uk
doi:10.3324/haematol.2019.234898
In this issue of Haematologica, Godavarthy et al.1 describe how the expression of CD44 on the surface of leukemic stem cells (LSC) and E-selectin on bone marrow (BM) endothelium are essential for the engraftment of LSC with- in the BM niche. They show how this interaction can pro- vide the LSC with protection from imatinib treatment. Importantly, disruption of this axis using an E-selectin inhibitor in combination with imatinib prevents LSC bind- ing to the endothelium and demonstrates superior eradica- tion of LSC in chronic myeloid leukemia (CML) compared with imatinib alone.
CML has been well characterized for a number of years, since the discovery of the Philadelphia chromosome and associated aberrant BCR-ABL signaling. This led to the rev- olutionary development of BCR-ABL-specific tyrosine kinase inhibitors such as imatinib. Tyrosine kinase inhibitors are highly effective at reducing the leukemic bur- den and disease progression, inducing remission and pro- longing survival of patients with chronic phase CML.2 Although very good control over the disease is gained in most chronic phase CML patients with tyrosine kinase inhibitor treatment, eradication of the LSC population, which sustains and repopulates the disease in patients, remains elusive.3
It has been established that the BM niche provides a sanc- tuary for LSC in which to thrive and avoid pharmacological interventions. There have been many studies showing how the niche adapts and is exploited during leukemic transfor- mation.4-6 By gaining, a better understanding of the interac- tions between LSC and their microenvironment, it may be possible to distinguish factors that favor survival of the leukemic cells and identify targets for improved drug ther- apy. One such strategy is to inhibit the homing and engraft- ment of LSC within the BM niche, without affecting nor- mal hematopoietic stem cells (HSC).7
The BM microenvironment is complex, due to the array of different cell types which reside there, including osteo- lineage cells, mesenchymal stem cells, endothelial cells, neurons and hematopoietic cells.8 In order to control and maintain homeostasis of the healthy BM niche, a multitude of cytokines and chemokines help determine HSC fate.8 In normal hematopoiesis homing and engraftment of HSC within the BM is a highly coordinated multistep process that requires activation of different adhesion receptors to maintain tight regulation. Selectins and integrins are very important within this process.9,10 Expression of integrins allows HSC to bind to vascular cell adhesion molecule-1 on BM endothelium and fibronectin on the extracellular matrix. Integrins, such as VLA4, also interact with E- and P- selectins, which are found constitutively expressed on the BM endothelium, and this interaction mediates HSC rolling and homing.10 Another important factor within this process is CXCL12; this chemkine functions as an HSC chemoat- tractant through its receptor CXCR4, which through
crosstalk with β1 and β2 integrins, mediates HSC homing and is required for stable engraftment.9 CD44 has also been linked to HSC homing; however, HSC that do not express CD44 can still home and engraft normally.11
In studies comparing the homing and engraftment of CML LSC to normal HSC, it has been shown that patients with CML have several adhesion abnormalities.12,13 LSC have defective β1 integrin function, despite normal expres- sion of VLA4 and VLA5, which decreases LSC adhesion to BM stroma.13 It has also been shown that primary CML progenitor cells have reduced CXCR4 expression and impaired chemotaxis towards CXCL12, as well as reduced CXCL12-mediated integrin adhesion.12 Despite these func- tional defects, LSC can still home and engraft within the BM and therefore must use alternative mechanisms.
Godavarthy et al.1 demonstrate a novel reciprocal link between the external cues from the BM microenvironment and BCR-ABL-specific LSC-intrinsic pathways. They show how this leads to modulation of the expression of LSC adhesion molecules and alters interactions with the vascu- lar niche. The authors confirm the interaction of BCR-ABL+ cells and the vascular endothelium by using very sophisti- cated in vivo microscopy of the calvarium of mice injected with human CML leukocytes. Using time-lapse imaging, they found that the contact time of the leukemic cells to the BM endothelium was reduced in mice treated with an E- selectin inhibitor (GMI-1271).
The authors replicated these findings in a transgenic
model, showing that BCR-ABL+ cells were situated signifi-
cantly further away from the endothelium if treated with
GMI-1271 and imatinib. Furthermore, after treatment with
GMI-1271 and imatinib, mice had improved survival, and
demonstrated reduced numbers of CML-initiating clones,
impaired short-term homing to the spleen and the BM,
reduced leukocyte counts, BCR-ABL+ myeloid cell counts
and spleen size. Further studies showed that inhibition of E-
selectin led to non-adhesion and an increase of Scl/Tal1
expression in BCR-ABL+ leukemia-initiating cells (LIC) in
vitro. Additionally, Scl/Tal1 negatively regulated the expres-
sion of CD44 on LIC, and overexpression of Scl/Tal1 on LIC
led to prolongation of survival in a murine model of CML,
similar to the improved survival with CD44-deficient
CML-initiating cells previously demonstrated by Krause et al.14
In vitro experiments demonstrated that CD44 was highly expressed in BCR-ABL+ cells compared to BCR-ABL– cells, and that when BCR-ABL+ cells were treated with GMI- 1271 alone or in combination with imatinib there was an increase in cells in G2-S-M phase and a decrease in the G0 phase of the cell cycle. This coincided with an increase in cell cycle promoter CDK6 and decreased expression of cell cycle inhibitor p16. Furthermore, BCR-ABL1 phosphorylat- ed SCL/TAL1 via the AKT signaling pathway. SCL/TAL1 regulated the activity of the CD44 regulatory element by
haematologica | 2020; 105(1)