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

Erb, Ulrike; Hikel, Julia; Meyer, Svenja; Ishikawa, Hiroshi; Worst, Thomas; Nitschke, Katja; Nuhn, Philipp; Porubský, Štefan; Weiß, Christel; Schroten, Horst; Adam, Rüdiger; Karremann, Michael

doi:10.3390/ijms21155491

Cited by 7 publications

(5 citation statements)

References 48 publications

(84 reference statements)

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“…CPE infected with JC polyomavirus release EVs carrying virions which target and infect astrocytes 149 . Intriguingly, CPE can be preconditioned by EVs derived from acute lymphoblastic leukemia cells to allow lymphoblast entry into the brain without altering the barrier function 150 . These findings underscore the importance of EV‐mediated periphery‐to‐brain signaling at the BCB in addition to the BBB.…”

Section: Brain–periphery Interactionmentioning

confidence: 97%

Extracellular Vesicles in neural cell interaction and CNS homeostasis

et al. 2021

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Central nervous system (CNS) homeostasis critically depends on the interaction between neurons and glia cells. Extracellular vesicles (EVs) recently emerged as versatile messengers in CNS cell communication. EVs are released by neurons and glia in activity-dependent manner and address multiple target cells within and outside the nervous system. Here, we summarize the recent advances in understanding the physiological roles of EVs in the nervous system and their ability to deliver signals across the CNS barriers. In addition to the disposal of cellular components via EVs and clearance by phagocytic cells, EVs are involved in plasticity-associated processes, mediate trophic support and neuroprotection, promote axonal maintenance, and modulate neuroinflammation. While individual functional components of the EV cargo are becoming progressively identified, the role of neural EVs as compound multimodal signaling entities remains to be elucidated. Novel transgenic models and imaging technologies allow EVtracking in vivo and provide further insight into EV targeting and their mode of action. Overall, EVs represent key players in the maintenance of CNS homeostasis essential for the life-long performance of neural networks and thus provide a wide spectrum of biomedical applications.

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Section: Brain–periphery Interactionmentioning

confidence: 97%

Extracellular Vesicles in neural cell interaction and CNS homeostasis

et al. 2021

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“…Recently, blast-derived extracellular vesicles have been hypothesized to foster malignant transformation of leukemic cells and facilitate transmigration across the blood-CSF-barrier by priming of choroid plexus cells [82,83]. Technological progress has enabled fluorescent labeling of extracellular vesicles [84] may also provide future biomarkers for CNS invasion and risk of CNS relapse.…”

Section: Soluble Biomarkers For Cns-allmentioning

confidence: 99%

“…Cytospin results could not be confirmed by PCR in 1 patient Soluble biomarkers Cerebrospinal fluid proteome during PEG-asparaginase treatment [ 78 ] Quantitative label-free LC-MS/MS (tryptic digest) Cross-sectional observation Newly diagnosed B- and T-ALL ( n = 4) and lymphoblastic lymphoma ( n = 1) Proteome profiling of CSF altertions during PEG-asparaginase treatment. 635 proteins (406 proteins with 2 or more peptides), here 35 protens had significantly altered intensities throughout day 0, day 8 and day 29 ( P < 0.05 following Benjamini-Hochberg correction) Cerebrospinal fluid proteome alterions comparing before vs after induction therapy [ 80 ] Quantitative label-free LC-MS/MS (tryptic digest) Cross-sectional observation Pediatric patients with confirmed CNS B-ALL ( n = 6) 428 proteins identified comparing pre vs post induction chemotherapy, here with 10 proteins being signficantly altered ( P < 0.05 in a paired t -test without correction of multiple comparisons) Extracellular vesicles (leukemia-derived exosomes for CSF-barrier transmigration) [ 83 ] Fluorescent microscopy Experimental In vitro model with human malignant choroids plexus papilloma cell line as blood-CSF-barrier and three ALL cell lines (SD-1, Nalm-6, P12-Ichikawa) Leukemia-derived exosomes may facilitate CNS invasion of ALL cell lines across the blod-CSF-barrer witout destruction of the barrier integrity microRNA [ 89 ] qPCR Cross-sectional observation Pediatric ALL and AML patients. Discovery cohort using CSF with CNS-ALL ( n = 4) and CNS-naive ALL ( n = 4) matched patients.…”

Section: Solution 1 – Better Biomarkersmentioning

confidence: 99%

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions

et al. 2022

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Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2–3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear – we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.

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“…Therefore, therapeutic monoclonal antibodies (mAbs) targeting CCR7 not only display a strong in vitro complement-dependent cytotoxicity (CDC) and an in vivo anti-tumor activity, but also show efficacy in eradicating leukemic cells from LN and CNS [ 120 ]. In addition to the CCR7-mediated CNS infiltration, the exosomes isolated from a T-ALL cell line P12 but not the B-cell acute lymphoblastic leukemia (B-ALL) cell lines facilitate CNS invasion across the blood–cerebrospinal fluid (CSF) barrier without disrupting the barrier integrity [ 121 ] ( Figure 2 C), highlighting the contribution of T-ALL-derived exosomes to CNS infiltration, although further studies are needed to clarify the molecular mechanisms.…”

Section: Leukemic Niches In T-allmentioning

confidence: 99%

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

Zhang

Yang

Zhang

2022

Cancers

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of hematological malignancy characterized by its high heterogeneity and potentially life-threatening clinical features. Despite the advances in risk stratification and therapeutic management of T-ALL, patients often suffer from treatment failure and chemotherapy-induced toxicity, calling for greater efforts to improve therapeutic efficacy and safety in the treatment of T-ALL. During the past decades, increasing evidence has shown the indispensable effects of leukemia-initiating cells (LICs) and leukemic niches on T-ALL initiation and progression. These milestones greatly facilitate precision medicine by interfering with the pathways that are associated with LICs and leukemic niches or by targeting themselves directly. Most of these novel agents, either alone or in combination with conventional chemotherapy, have shown promising preclinical results, facilitating them to be further evaluated under clinical trials. In this review, we summarize the latest discoveries in LICs and leukemic niches in terms of T-ALL, with a particular highlight on the current precision medicine. The challenges and future prospects are also discussed.

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

Cited by 7 publications

References 48 publications

Extracellular Vesicles in neural cell interaction and CNS homeostasis

Extracellular Vesicles in neural cell interaction and CNS homeostasis

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

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