Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance

Abstract

The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. We now report in contrast, E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. Using acute myeloid leukemia (AML) mouse models, we show AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of prosurvival signaling through AKT/NF-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Absence (in Sele −/− hosts) or therapeutic blockade of E-selectin using small molecule mimetic GMI-1271/Uproleselan effectively inhibits this niche-mediated pro-survival signaling, dampens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone, whilst protecting endogenous HSC.

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

“…However, targeting the interaction between LSC and selectins on endothelial cells is an area of active research as upregulation of E-selectin on endothelial cells has been associated with LSC survival and chemotherapy resistance [ 20 , 111 ]. Inhibition of E-selectin with the small molecule GMI-1271 (uproleselan) in combination with chemotherapy has been shown to prolong survival in a mouse model of AML [ 21 ]. Mechanistically, Barbier et al showed in murine experiments using adoptive transfer of HSCs that had been retrovirally transduced with the human MLL-AF9 fusion oncogene that AML blasts exhibit an increased E-selectin-binding potential that enabled retention of AML blasts within the bone marrow and could contribute to chemotherapy resistance [ 21 ].…”

“…Inhibition of E-selectin with the small molecule GMI-1271 (uproleselan) in combination with chemotherapy has been shown to prolong survival in a mouse model of AML [ 21 ]. Mechanistically, Barbier et al showed in murine experiments using adoptive transfer of HSCs that had been retrovirally transduced with the human MLL-AF9 fusion oncogene that AML blasts exhibit an increased E-selectin-binding potential that enabled retention of AML blasts within the bone marrow and could contribute to chemotherapy resistance [ 21 ]. Furthermore, treatment with GMI-1271 increased mobilization of AML blasts from the bone marrow and sensitized them to the effects of cytarabine with a concurrent reduction in the number of LSCs resulting in a survival advantage compared to control mice [ 21 ].…”

“…Mechanistically, Barbier et al showed in murine experiments using adoptive transfer of HSCs that had been retrovirally transduced with the human MLL-AF9 fusion oncogene that AML blasts exhibit an increased E-selectin-binding potential that enabled retention of AML blasts within the bone marrow and could contribute to chemotherapy resistance [ 21 ]. Furthermore, treatment with GMI-1271 increased mobilization of AML blasts from the bone marrow and sensitized them to the effects of cytarabine with a concurrent reduction in the number of LSCs resulting in a survival advantage compared to control mice [ 21 ]. Similar results were achieved in mice with E-selectin gene-deletion ( Sele −/− ) further supporting the mechanism of action of GMI-1271 via E-selectin inhibition [ 21 ].…”

“…Furthermore, treatment with GMI-1271 increased mobilization of AML blasts from the bone marrow and sensitized them to the effects of cytarabine with a concurrent reduction in the number of LSCs resulting in a survival advantage compared to control mice [ 21 ]. Similar results were achieved in mice with E-selectin gene-deletion ( Sele −/− ) further supporting the mechanism of action of GMI-1271 via E-selectin inhibition [ 21 ]. Additionally, treatment with GMI-1271 blocks signaling via the PI3K/AKT/NF-kB and RAS/MAPK/ERK pathways; two pathways that have been associated with AML blast survival [ 21 , 112 ].…”

“…Over the past two decades the role of adhesion molecules and cytokines in both the homing of HSCs into the bone marrow and the development of leukostasis has been increasingly characterized [ 18 ]. Especially endothelial selectins that promote adherence of leukemic blasts to the vascular endothelium have been identified as essential players not only in the development of leukostasis but also in chemotherapy resistance and leukemic stem cell (LSC) survival [ 18 , 19 , 20 , 21 ]. Herein, we provide a brief overview of the interaction of HSCs and LSCs in the bone marrow environment under physiologic circumstances as well as in AML before shifting to the processes in the peripheral circulation leading to DIC, TLS, and leukostasis and a discussion of potential therapeutic targets.…”