A comprehensive clinical study of integrins in acute lymphoblastic leukemia indicates a role of α6/CD49f in persistent minimal residual disease and α5 in the colonization of cerebrospinal fluid

Scharff, Bibi F. S. S.; Modvig, Signe; Thastrup, Maria; Levinsen, Mette; Degn, Matilda; Ryder, Lars P.; Schmiegelow, Kjeld; Christensen, Carl Jørgen; Marquart, Hanne Vibeke

doi:10.1080/10428194.2020.1731500

Cited by 14 publications

(23 citation statements)

References 15 publications

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“…A recent study investigating the mRNA and protein surface expression of integrins in ALL failed to confirm the proposed association between MRD and α4/CD49d or α5 mRNA in a large patient group. The strongest association with MRD was instead found for α6/CD49f (79). The reason for these discrepancies is currently unknown.…”

Section: Adhesion and Chemoresistance Of All Within The Bone Marrowmentioning

confidence: 92%

“…However, integrin regulation is highly complex and what defines integrin function is integrin activation and the resulting ligand affinity of specific integrin heterodimers, rather than the levels of individual integrin subunits per se. Hence, studies addressing affinity states of α4:β1, such as the work of Shalapour et al (75) are likely closer to revealing the association of α4:β1with MRD than studies based entirely on expression profiles, such as the work of Scharff et al Also, the work of Scharff et al did not specifically address Ph + ALL, which may be the reason why an association between MRD and α5 was not seen (79).…”

Section: Adhesion and Chemoresistance Of All Within The Bone Marrowmentioning

confidence: 99%

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Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System

et al. 2020

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Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood. Despite a significantly improved prognosis over the last decade with a 5-years survival rate of ∼90%, treatment-related morbidity remains substantial and relapse occurs in 10-15% of patients (1). The most common site of relapse is the bone marrow, but early colonization and subsequent reoccurrence of the disease in the central nervous system (CNS) also occurs. Integrins are a family of cell surface molecules with a longstanding history in cancer cell adherence, migration and metastasis. In chronic lymphoblastic leukemia (CLL), the VLA-4 integrin has been acknowledged as a prognostic marker and mounting evidence indicates that this and other integrins may also play a role in acute leukemia, including ALL. Importantly, integrins engage in anti-apoptotic signaling when binding extracellular molecules that are enriched in the bone marrow and CNS microenvironments. Here, we review the current evidence for a role of integrins in the adherence of ALL cells within the bone marrow and their colonization of the CNS, with particular emphasis on mechanisms adding to cancer cell survival and chemoresistance.

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Section: Adhesion and Chemoresistance Of All Within The Bone Marrowmentioning

confidence: 92%

Section: Adhesion and Chemoresistance Of All Within The Bone Marrowmentioning

confidence: 99%

Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System

et al. 2020

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“…As blocking of integrins did not affect uptake of the BCP-ALL-derived exosomes, binding and uptake to HiBCPP cells may obviously follow multiple pathways and differ between exosomes from the various cell lines. Although we did not quantify the expression of the various integrins on exosomes, we hypothesize that these were prevalent on the extracellular vesicles, since all three ALL cell lines express the evaluated integrins [36][37][38].…”

Section: Mechanisms Of Exosome Uptake To Hibcpp Cellsmentioning

confidence: 97%

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

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Hikel

Meyer

et al. 2020

IJMS

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Central nervous System (CNS) disease in pediatric acute lymphoblastic leukemia (ALL) is a major concern, but still, cellular mechanisms of CNS infiltration are elusive. The choroid plexus (CP) is a potential entry site, and, to some extent, invasion resembles CNS homing of lymphocytes during healthy state. Given exosomes may precondition target tissue, the present work aims to investigate if leukemia-derived exosomes contribute to a permissive phenotype of the blood-cerebrospinal fluid barrier (BCSFB). Leukemia-derived exosomes were isolated by ultracentrifugation from the cell lines SD-1, Nalm-6, and P12-Ichikawa (P12). Adhesion and uptake to CP epithelial cells and the significance on subsequent ALL transmigration across the barrier was studied in a human BCSFB in vitro model based on the HiBCPP cell line. The various cell lines markedly differed regarding exosome uptake to HiBCPP and biological significance. SD-1-derived exosomes associated to target cells unspecifically without detectable cellular effects. Whereas Nalm-6 and P12-derived exosomes incorporated by dynamin-dependent endocytosis, uptake in the latter could be diminished by integrin blocking. In addition, only P12-derived exosomes led to facilitated transmigration of the parental leukemia cells. In conclusion, we provide evidence that, to a varying extent, leukemia-derived exosomes may facilitate CNS invasion of ALL across the BCSFB without destruction of the barrier integrity.

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“…Integrin a 6 dimerizes with b 1 to form VLA-6 (186) or with b 4 to form a 6 b 4, which is also known as TSP-180 (187). a 6 has been suggested to be a biomarker for minimal residual disease since it is expressed on pre-B-ALL at diagnosis, and the signal is preserved or expressed with a higher intensity after therapy (10,188). a 6 was found to be expressed significantly more strongly not only in relapsed B-ALL but also in ecotropic viral integration site-1 positive (EVI1 + ) AML cases.…”

Section: Integrin a 5 (Cd49e)mentioning

confidence: 99%

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

et al. 2020

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The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell–cell or cell–extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.

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A comprehensive clinical study of integrins in acute lymphoblastic leukemia indicates a role of α6/CD49f in persistent minimal residual disease and α5 in the colonization of cerebrospinal fluid

Cited by 14 publications

References 15 publications

Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System

Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

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