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Editorials
Figure 1. This schematic demonstrates the effects of E-selectin inhibition within the bone marrow microenvironment and the impact upon chronic myeloid leukemia stem cells and mechanistically how this is controlled by the SCL/TAL1 – CD44 axis. HPC: hematopoietic progenitor cell; HSC; hematopoietic stem cell; LSC: leukemic stem cell.
acting as a transcriptional repressor leading to decreased expression of CD44, decreased adhesion to the vascular niche and an increase in cycling LSC.
Interestingly, higher expression of CD44 was demon- strated in BCR-ABL cells specifically harboring the T315I mutation, which correlated with increased binding to E- selectin, with a larger amount of adherent cells in G0. The authors suggest that the increased expression of CD44 and increased binding to E-selectin may contribute to LSC dor- mancy and resistance to tyrosine kinase inhibitors.
Finally, relevance to human CML was established as leukocytes from patients with CML had higher transcrip- tional expression of SCL/TAL1 and lower CD44 expression compared to those from healthy individuals. Analyses of published datasets suggest a trend that expression of SCL/TAL1 and CD44 may correlate with disease stage and survival in CML patients; however, larger cohorts and fur- ther experimental data are required to confirm this.
The important experiments presented by Godavarthy et al. establish the mechanism of increased expression of
CD44 on BCR-ABL1+ cells. They further showed that dislo- cation of BCR-ABL1+ cells from the niche, via inhibition of E-selectin binding, increased BCR-ABL+ cell cycle progres- sion and increased responsiveness to imatinib therapy.1
Inhibition of E-selectin has been shown to have therapeu- tic utility in other cancer types, such as acute myeloid leukemia and solid tumors in which it is thought to have a role in metastasis.15 In acute myeloid leukemia, the leukemic blast cells bind to E-selectin on the endothelium and this activates leukemic pathways that contribute to chemotherapy resistance.16 Currently, GMI-1271 is in a phase I/II clinical trial to treat acute myeloid leukemia in combination with chemotherapy to disrupt leukemia sur- vival pathways and sensitize the leukemic cells to chemotherapy (ClinicalTrials.gov Identifier: NCT02306291)
E-selectin has also been implicated in the development of metastasis to the lungs from primary solid tumors, such as breast17 and colon18 cancer. It is hypothesized that, during the premetastatic stage, the primary tumors secrete soluble factors, which induce an inflammatory response in the
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