Flow cytometric detection of leukemic blasts in cerebrospinal fluid predicts risk of relapse in childhood acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology study

Thastrup, Maria; Marquart, Hanne Vibeke; Levinsen, Mette; Grell, Kathrine; Abrahamsson, Jonas; Albertsen, Birgitte Klug; Frandsen, Thomas Leth; Harila‐Saari, Arja; Lähteenmäki, Päivi; Niinimäki, Riitta; Pronk, Cornelis Jan; Ulvmoen, Aina; Vaitkevičienė, Goda; Taskinen, Mervi; Schmiegelow, Kjeld

doi:10.1038/s41375-019-0570-1

Cited by 51 publications

(84 citation statements)

References 29 publications

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“…Disruption of the brain barriers was a late event in a mouse model of CNS leukemia [5], correlating to in vivo findings where parenchymal metastases occur only occasionally during early stages [4]. However, subclinical CNS infiltration in pediatric ALL at diagnosis is more frequent than previously assumed, with most of these patients presenting without neurological signs of disturbed blood-CNS barriers [26,27]. Therefore, transmigration of lymphoblasts facilitated by exosome-associated conditioning of the barriers might well be due to more sophisticated mechanisms than just disruption of tight junctions and barrier breakdown, but e.g., by the induction of receptor expression or cytokine signaling [3,4,18].…”

Section: Exosome Conditioning Does Not Alter Bcsfb Integritysupporting

confidence: 55%

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

Erb

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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Section: Exosome Conditioning Does Not Alter Bcsfb Integritysupporting

confidence: 55%

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

Erb

Hikel

Meyer

et al. 2020

IJMS

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“…123 Acute lymphoblastic leukemia blasts are typically detected in CSF by morphologic evaluation of cytospin samples. Flow cytometric analysis of CSF improved ALL blast detection, and positive results were associated with a higher incidence of any relapse, 124 although another study failed to show such an association. 125…”

Section: Central Nervous System-directed Therapymentioning

confidence: 99%

Pediatric acute lymphoblastic leukemia

Inaba¹,

Mullighan²

2020

haematol

400

267

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The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.

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“…However, many times it is hard to differentiate between these lesions and CNS infections or neurodegenerative disorders, which are also common in patients with acute leukemia (204,205). These imaging challenges, associated with the difficulties faced by the LP analysis oftentimes delay the diagnostic and the beginning of treatment in CNS leukemia patients, much to the disadvantage in the quality of life and survival of these patients (206,207).…”

Section: Cns Leukemia-diagnostic Toolsmentioning

confidence: 99%

A narrative review of central nervous system involvement in acute leukemias

Deak¹,

Gorcea-Andronic²,

Sas³

et al. 2021

Ann Transl Med

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Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although

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Flow cytometric detection of leukemic blasts in cerebrospinal fluid predicts risk of relapse in childhood acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology study

Cited by 51 publications

References 29 publications

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

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

Pediatric acute lymphoblastic leukemia

A narrative review of central nervous system involvement in acute leukemias

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