Cleaved L-selectin concentrations in meningeal leukaemia

doi:10.1016/S0140-6736(95)90276-7

The Lancet

Volume 345, Issue 8945, 4 February 1995, Pages 286-289

https://doi.org/10.1016/S0140-6736(95)90276-7 Get rights and content

Abstract

Involvement of the central nervous system has important therapeutic implications in acute leukaemia. Because the identification of blast cells in cerebrospinal fluid (CSF) is often difficult, there is a need for sensitive markers of leukaemic infiltration. Since the shed form of L-selectin (sL-selectin) is frequently increased in acute leukaemia (sL-selectin* leukaemia), we examined whether assay of sL-selectin in CSF could improve our ability to detect such meningeal involvement. CSF sL-selectin was significantly (p<0·001) higher in 15 patients with sL-selectin⁺ meningeal leukaemia (median 60 ng/mL, range 34-150) than in 20 patients with acute leukaemia without meningeal involvement (12 ng/mL, 1-39) or 88 control patients (14 ng/mL, 0-37). Serial measurements of sL-selectin in patients with sL-selectin⁺ leukaemic meningitis showed increased CSF concentrations of the cleaved receptor in 4 patients with therapy-resistant meningeal leukaemia and sustained normal concentrations in 9 patients in remission. Our results suggest that CSF sL-selectin may be a useful marker in the detection of meningeal involvement by blast cells in patients with sL-selectin⁺ leukaemia.

References (18)

D. Pinkel et al.
Prevention of meningeal leukemia in children
Blood
(1994)
W. Bleyer
Central nervous system leukemia
Pediatr Clin North Am
(1988)
Dh Adams et al.
Leucocyte-endothelial interactions and regulation of leucocyte migration
Lancet
(1994)
T. Springer
Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm
Cell
(1994)
O. Spertini et al.
ELISA for quantitation of L-selectin shed from leucocytes in vivo
J Immunol Methods
(1992)
O. Spertini et al.
High levels of the shed form of L-selectin (sL-selectin) are present in patients with acute leukemia and inhibit blast cell adhesion to activated endothelium
Blood
(1994)
Y. Komada et al.
Shedding of CD9 antigen into cerebrospinal fluid by acute lymphoblastic leukemia cells
Blood
(1990)
H. Mahmoud et al.
Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia
N Engl J Med
(1993)

There are more references available in the full text version of this article.

Cited by (27)

T cell acute lymphoblastic leukemia (T-ALL): New insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies
2018, Blood Reviews
Citation Excerpt :
As both MMPs have been described to be over-expressed in different leukemic cells, it is reasonable to speculate that similar MMP-dependent mechanisms occur during infiltration of different types of leukemia. Taken together, L-selectin shedding might be an essential difference defining the infiltration capacities of T-ALL and AML cells as soluble L-selectin is only found in CSF and plasma of AML patients [213]. By contrast, L-selectin surface expression in T-ALL is associated with liver infiltration; whereas in AML, it is associated with lymph node and skin infiltration [214].
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% and 25% of total childhood and adult ALL cases, respectively. During T-ALL, patients are at risk of organ infiltration by leukemic T-cells. Infiltration is a major consequence of disease relapse and correlates with poor prognosis. Transendothelial migration of leukemic cells is required to exit the blood stream into target organs. While mechanisms of normal T-cell transmigration are well known, the mechanisms of leukemic T-cell extravasation remain elusive; but involvement of chemokines, integrins and Notch signaling play critical roles. Here, we summarize current knowledge about molecular mechanisms of leukemic T-cell infiltration with special emphasis on the newly identified subtype early T-cell-progenitor (ETP)-ALL. Furthermore, we compare the extravasation potential of T-ALL cells with that of other hematologic malignancies such as B-ALL and acute myeloid leukemia (AML).
E-selectin as a target for drug delivery and molecular imaging
2012, Journal of Controlled Release
Citation Excerpt :
It is also well documented today that E-selectin is deeply implicated in many disorders including inflammatory diseases, cardiovascular disorders, cancer and metastasis. On the other hand, there is little evidence for the direct involvement of L-selectin in pathology, although some studies have reported variations in levels of the receptor and/or its soluble form (sL-selectin) in serum in some patients with HIV-infection [20], insulin-dependent diabetes mellites [21], meningeal leukemia [22], multiple sclerosis [23] and sepsis [20]. However, its soluble form, sL-selectin, was found to be decreased in patients with Kawasaki Syndrome and in patients with risk factors for acute ischemic stroke even in the absence of disease [24].
E-selectin, also known as CD62E, is a cell adhesion molecule expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation and in the adhesion of metastatic cancer cells to the endothelium. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes.
E-selectin has been chosen as a target for several therapeutic and medical imaging applications, based on its expression in the vicinity of inflammation, infection or cancer. These systems for drug delivery and molecular imaging include immunoconjugates, liposomes, nanoparticles, and microparticles prepared from a wide range of starting materials including lipids, synthetic polymers, polypeptides and organo-metallic structures.
After a brief introduction presenting the selectin family and their implication in physiology and pathology, this review focuses on the formulation of these new delivery systems targeting E-selectin at a molecular level.
Selectins - An emerging target for drug delivery
2004, Advanced Drug Delivery Reviews
Selectins are multifunctional adhesion molecules that mediate the initial interactions between circulating leukocytes and cells of the endothelium. First identified over a decade ago, selectins have provided insight into areas as diverse as normal lymphocyte homing, leukocyte recruitment during inflammatory responses, carbohydrate ligand biosynthesis and adhesion-mediated signalling. Of late, selectins were introduced as targets for drug delivery in the development of new anti-inflammatory therapeutics and in anti-cancer therapy. This review will examine the selectins and their ligands with a focus on recent findings on their role in physiology and pathophysiology as well as the emerging role of selectins as targets in controlled drug delivery.
Soluble leukocyte selectin in the analysis of pleural effusions
2001, Chest
Citation Excerpt :
Dagdemir et al16 studied children with CNS leukemia with the presence of blasts and noted elevated sL-selectin levels (12.41 ± 2.14 ng/mL) compared to leukemic patients without CSF involvement (1.34 ± 0.21 ng/mL) and normal control subjects (1.46 ± 0.18 ng/mL). Stucki et al17 found similar results with higher CSF sL-selectin levels in 15 patients with meningeal leukemia (median of 60 ng/mL) than 20 leukemia patients without meningeal involvement (median of 12 ng/mL). This study demonstrated several important points about the use of sL-selectin in the analysis of PF.
To determine if soluble leukocyte selectin (sL-selectin) levels in serum and pleural fluid (PF) are an inflammatory marker that differentiates pleural effusion transudates from exudates.
sL-selectin PF and serum levels were measured in consecutive patients and compared to established criteria.
A tertiary-care military medical center.
One hundred twenty patients undergoing diagnostic or therapeutic thoracentesis.
PF and serum samples were collected during thoracentesis and analyzed separately for sL-selectin levels. Results were compared with clinical diagnosis and established PF criteria including the criteria of Light et al, cholesterol ratio, total bilirubin ratio, and albumin gradient.
sL-selectin levels in PF and serum were determined in 109 patients. By clinical diagnosis, mean ± SD PF sL-selectin levels were 200.2 ± 124.3 ng/mL in transudates and 496.8 ± 379.2 ng/mL in exudates (p < 0.001). By the criteria of Light et al, mean PF sL-selectin levels were 195.7 ± 105.2 ng/mL in transudates and 448.2 ± 367.6 ng/mL in exudates (p < 0.001). Mean sL-selectin PF to serum ratios were 0.31 ± 0.17 in transudates and 0.72 ± 0.31 in exudates (p < 0.001) by clinical criteria, and 0.31 ± 0.18 in transudates and 0.64 ± 0.33 in exudates (p < 0.001) by the criteria of Light et al. No significant difference was noted with serum sL-selectin levels between groups.
sL-selectin is an inflammatory marker that differentiates transudates from exudates in pleural effusions and is a sensitive indicator for PF analysis.
Endothelial cell activation by myeloblasts: Molecular mechanisms of leukostasis and leukemic cell dissemination
2001, Blood
Citation Excerpt :
Acute leukemias are heterogeneous regarding the origin of the neoplastic clone, cytogenetic abnormalities, clinical presentation, response to treatment, and biologic behavior.40 Dissemination of blast cells in extramedullary sites and leukostasis are major concerns in the treatment of patients with AML.40–44 The study of myeloblast–endothelial cell interactions reported here may give new insights into the mechanisms of such complications.
Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-α. Inhibition studies showed that multiple adhesion receptors—including L-selectin, E-selectin, VCAM-1, and CD11/CD18—were involved in blast cell adhesion to TNF-α–activated endothelium. Leukemic cells were then cocultured at 37°C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-α and IL-1β, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells.
Glycoprotein-inspired materials promote the proteolytic release of cell surface L-selectin
1998, Bioorganic and Medicinal Chemistry
The proteolytic release, or shedding, of a cell surface protein can serve a regulatory role; the process liberates a soluble form of the protein into circulation while downregulating its cell surface concentration. The characteristics that render a protein susceptible to proteolytic cleavage are not known. We hypothesized that the clustering of a protein at the cell surface might target it for proteolysis. To test this hypothesis, we synthesized molecules that display multiple copies of sulfated galactose residues, termed neoglycopolymers, that are designed to mimic natural ligands for the cell adhesion protein l-selectin. We found that treatment of human neutrophils with the neoglycopolymers resulted in a dose-dependent loss of l-selectin from the cell surface, while monovalent compounds and unsulfated neoglycopolymers had no effect. Because l-selectin is an important mediator in the inflammatory response, such compounds could lead to novel antiinflammatory drugs. Moreover, molecules that control receptor shedding can be used to alter cellular responsiveness to specific ligands or to promote responses at distal sites; consequently, these results have broad implications for regulating the location and presentation of important biomolecules.

View all citing articles on Scopus

View full text

Cleaved L-selectin concentrations in meningeal leukaemia

Abstract

Blood

Pediatr Clin North Am

Lancet

Cell

J Immunol Methods

Blood

Blood

Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia

N Engl J Med