A Small Molecule α4β1/α4β7Antagonist Differentiates between the Low-Affinity States of α4β1and α4β7: Characterization of Divalent Cation Dependence

Egger, Linda A.; Cao, Jun; McCallum, Christine; Kidambi, Usha; Riper, Gail Van; McCauley, Ermengilda; Mumford, Richard A.; Lanza, Thomas J.; Lin, Linus S.; Laszlo, Stephen E. de; Young, Darrin J.; Yang, Gee-Gwo; Dean, Dennis C.; Raab, Conrad E.; Wallace, Mark N.; Jones, Allen N.; Schmidt, John A.; Pepinsky, R. Blake; Scott, Daniel M.; Lee, Wen‐Cherng; Cornebise, Mark; Detmers, Patricia A.

doi:10.1124/jpet.102.047704

Cited by 8 publications

(4 citation statements)

References 35 publications

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“…6C and Supplementary Fig. S9H) could be reduced by an ITGA4 inhibitor (TR-14035) [36,37]. Notably, TR-14035 also reduced chemoresistance in the NC group, indicating that ITGA4 inhibitors further sensitized the cells to chemotherapy.…”

Section: Itga4 Is the Direct Target Of Mettl3 In Aml Chemoresistancementioning

confidence: 94%

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

Xia

et al. 2022

Leukemia

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Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m6A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m6A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m6A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m6A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors.

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Section: Itga4 Is the Direct Target Of Mettl3 In Aml Chemoresistancementioning

confidence: 94%

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

Xia

et al. 2022

Leukemia

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“…Interestingly, the method has only recently been used in characterization of the binding of ligands with the αvβ6 integrin 19,20 and has only been used sparingly in the integrin field. 21,22 Therefore, studies were completed to aid in the identification and profiling of high-affinity and αvβ6 selective small-molecule RGD mimetics by validation of the most appropriate test systems to investigate these characteristics within the constraints of throughput. In addition, to determine the dissociation profiles of small-molecule RGD mimetics from the αvβ6 integrin, the design and implementation of a novel radioligand integrin binding assay are described.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determining the True Selectivity Profile of αv Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem

2017

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The arginyl-glycinyl-aspartic acid (RGD) integrin subfamily contains five members that partner with the αv subunit: αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8. Within the αv integrins, the epithelially restricted αvβ6 has been identified as playing a key role in the activation of transforming growth factor β that is hypothesized to be pivotal in the development of idiopathic pulmonary fibrosis (IPF). As part of a drug discovery program to identify a selective αvβ6 RGD mimetic for IPF, cell adhesion and radioligand binding assays were investigated to screen compounds to determine affinity and αv integrin selectivity. In this study, a pan-αv radioligand was characterized against all the αv integrins and used to determine accurate selectivity profiles for literature and novel RGD ligands, as well as enable an early readout on αvβ6 dissociation kinetics. It has been shown that while cell adhesion offers a high throughput and reliable format for ranking compounds, there are downsides to this format when comparing selectivity across αv integrins. By accurately defining the relationship between these assay formats, a medicinal chemistry effort has identified novel, high-affinity, and selective αvβ6 RGD mimetics with slow dissociation kinetics, with the potential to be developed into clinical candidates for IPF.

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“…Mn 2+ is shown to be a very potent initiator of many integrin‐mediated cell adhesion events, and only concentrations in the micromolar range are required for achieving cell adhesion in different cell lines (12, 13). The presence of such concentrations of extracellular Mn 2+ induces the formation of the activated state of beta‐1 integrins (10, 14). Mg 2+ is also shown to be important for promoting ligand binding of integrins, whereas Ca 2+ usually, but not always, has an inhibitory effect on adhesion (4).…”

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confidence: 99%

Mn²⁺ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF‐1, and SDF‐1α

Slørdahl

Hov

Holt

et al. 2008

European J of Haematology

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Adhesion of multiple myeloma (MM) cells in the bone marrow (BM) is important for the growth and survival of the myeloma cells. Very late antigen-4 (VLA-4) is one of the main adhesion receptors that mediate MM cell binding to fibronectin (FN). In this study we have examined the effect of divalent cations on adhesion of MM cells to FN, and compared this type of adhesion with the adhesion induced by the cytokines HGF, IGF-1 and SDF-1alpha. Mn(2+) induced adhesion in all cell lines tested. Cytokine- and Mn(2+)-induced VLA-4-mediated adhesion were different in many respects, including binding specificity, adhesion kinetics and the activation state of VLA-4. To study a potential role of divalent cations in vivo, we measured the concentrations of divalent cations in BM plasma from 14 MM patients. We also found that Mn(2+)-mediated adhesion to FN activated the MAPK pathway, indicating that the interaction of MM-cells with FN mediated by Mn(2+) could play a critical role for growth and proliferation. In conclusion, this study shows a potential important role of divalent cations in MM cell biology and supports earlier studies pointing to activated VLA-4 as a key for homing of MM cells to the BM.

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A Small Molecule α₄β₁/α₄β₇Antagonist Differentiates between the Low-Affinity States of α₄β₁and α₄β₇: Characterization of Divalent Cation Dependence

Cited by 8 publications

References 35 publications

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

Determining the True Selectivity Profile of αv Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem

Mn²⁺ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF‐1, and SDF‐1α

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A Small Molecule α4β1/α4β7Antagonist Differentiates between the Low-Affinity States of α4β1and α4β7: Characterization of Divalent Cation Dependence

Cited by 8 publications

References 35 publications

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4

Determining the True Selectivity Profile of αv Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem

Mn2+ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF‐1, and SDF‐1α

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A Small Molecule α₄β₁/α₄β₇Antagonist Differentiates between the Low-Affinity States of α₄β₁and α₄β₇: Characterization of Divalent Cation Dependence

Mn²⁺ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF‐1, and SDF‐1α