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NEOPLASIA
From the Division and Central Laboratory of Hematology,
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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)- The hyperleukocytosis that can be observed in acute
myeloid leukemia (AML) may lead to leukostasis, a life-threatening
complication caused by leukemic cell sludging in blood
capillaries.1,2 In the absence of treatment, cellular
hyperviscosity caused by extreme leukocyte count elevation may rapidly
lead to multiple organ failure and death. The mechanisms at the origin
of leukostasis are poorly understood. Size and stiffness of blast cells
might play a role; leukostasis is more frequently observed in patients with AML or chronic myelocytic leukemia than in patients with acute
lymphoblastic or chronic lymphocytic leukemia.1 However, additional factors may also be involved, as indicated by leukostasis development in the absence of hyperleukocytosis or by the frequent failure of therapeutic leukapheresis in controlling
leukostasis.2-4
Although little is known about the molecular mechanisms that regulate
myeloblast migration to tissues, adhesion receptors are likely to play
an important role in this process.5,6 In vitro and in vivo
observations have shown that the initial phase of normal leukocyte
recruitment at site of inflammation is mediated by selectins that
cooperate with integrins to mediate leukocyte rolling along vascular
endothelium.7-12 During rolling on selectins, leukocytes
are exposed to inflammatory mediators that induce integrin activation
and facilitate integrin-mediated firm adhesion.13 Mention
should be made that endothelium exposure to inflammatory cytokines such
as tumor necrosis factor (TNF)- Adhesion studies performed under static conditions have shown that
myeloblast adhesion to cytokine-activated endothelium is mediated by
E-selectin, ICAM-1, and VCAM-1.6 L-selectin may play a
role in initiating the attachment of L-selectin+ blast
cells to cytokine-activated endothelium.30 In these latter investigations, endothelial cell preactivation by exogenous cytokine was required to observe blast cell adhesion. In the current study, we
have investigated the mechanisms involved in the adhesion of AML blast
cells to resting endothelium. We show that myeloblasts can activate
endothelial cells and promote their own adhesion to the vascular wall
by cytokine secretion and endothelial cell activation through
endothelial cell adhesion receptors.
Antibodies
Patients and myeloblast immunophenotypic analysis
Blast cell attachment assay to TNF- Recruitment of blast cells on unactivated endothelial cell monolayers. Leukemic blast cell recruitment on unactivated endothelial cells was assessed by coculturing endothelial cell monolayers in 21 cm2 Petri dishes with 8 × 106 blast cells in 6 mL medium for 0.75 hour, 3 hours, 6 hours, and 24 hours. Endothelial and blast cells were cultured in 199 medium containing 10% FCS (Myoclone Superplus; Gibco, Basel, Switzerland), 50 UI/mL porcine intestinal mucosa heparin (Leo Pharmaceutical Products, Ballrup, Denmark), 15 mM Hepes, 2 mM L-glutamine, penicillin, and streptomycin (all from Gibco). After coculture, Petri dishes were placed in PBS-2% glutaraldehyde. After overnight fixation, Petri dishes were washed and adherent blasts were counted. Coculture of blast cells with endothelial cell monolayers The ability of blast cells to induce endothelial cell adhesion receptor expression was evaluated by coculturing blast cells with confluent endothelial cell monolayers for various times in 25-cm2 plastic flasks. Cells (107 blast cells/flask) were cocultured in 7.5 mL 199 medium containing 10% FCS, heparin, Hepes, L-glutamine, penicillin, and streptomycin. After the removal of culture medium and nonadherent cells, adherent blast cells were detached from endothelial cell monolayers by gentle washing and processed for immunophenotypic analysis. In parallel, endothelial cells were detached from plastic flasks with PBS containing 5 mM EDTA, washed twice in RPMI medium/5% FCS, and stained with appropriate mAbs. Immunophenotypic analysis was performed by flow cytometry, as described above. Endothelial cell adhesion receptor expression was evaluated using non-cross-blocking FITC-labeled mAbs in experiments evaluating the effect of adhesion blocking mAbs on endothelial cell activation by blast cells. Results were compared to those obtained using endothelial cells grown in medium alone. For several experiments, culture media were collected after 3, 6, or 24 hours of culture, centrifuged, passed through a 0.2 µm filter (Millipore), and run on Detoxigel (Pierce, Oud-Beijerland, The Netherlands) to obtain endotoxin-free culture media. In some experiments, direct contact between leukemic blast cells and endothelial cells was prevented using a membrane with 0.4 µm pores (Transwell cell culture chamber; Costar, Badhoevedorp, The Netherlands). In 3 experiments, the percentage of apoptotic myeloblasts was assessed by cell staining with FITC-conjugated AnnexinV and propidium iodide using the AnnexinV kit (Immunotech).36 The percentage of apoptotic cells did not significantly increase after 24 hours of coculture with endothelial cells (20% [t = 0 h] vs 21% after 24 hours of coculture; 11% vs 8% and 13% vs 16%).Statistical analysis Unpaired Student t tests or Mann-Whitney tests were used for group comparison. When 3 or more groups were compared, differences between treatments were evaluated by analysis of variance (ANOVA) and the Bonferroni multiple comparison test or the Kruskal-Wallis nonparametric ANOVA test. P < .05 was considered significant. Data are shown as mean ± 1 SD.
Expression of adhesion molecules by myeloblasts The following FAB subtype distribution (subtype, number of patients) was observed among the 78 patients investigated in this study: M0, 3; M1, 10; M2, 24; M3, 4; M4, 30; M5, 7. Expression of the various adhesion molecules was heterogenous among the various FAB subtypes and also within each of them (Table 1, Figure 1). For example, there was a significant heterogeneity of L-selectin expression (P = .02; Figure 1 and Table 1) with higher levels detected on M0 (median, 31%) or M1 (50%) blast cells and lower levels on M2 (12%), M3 (8%), M4 (17%), or M5 (6%) blast cells. Heterogeneity was also seen for CD11b expression (P = .05), with higher levels on M5 (median, 90%) blast cells than among other AML categories (M0, 3%; M1, 10%; M2, 22%; M3, 4%; M4, 29%; M5, 7%). Finally, there were significant variations in CD49d (M0, 96%; M1, 94%; M2, 89%; M3, 72%; M4, 75%; M5, 92%; P = .007) and in CD49f expression (M0, 44%; M1, 34%; M2, 23%; M3, 12%; M4, 8%; M5, 1%; P = .008) (Table 1, Figure 1). Blast cells from 15 patients with AML were analyzed for the expression of PSGL-1. A strong expression of this marker was observed in most cases (median, 95%; range, 32%-100%; n = 15).
Selectins and integrins mediate the attachment of blast cells to
TNF-  (100 U/mL
TNF- for 6 hours at 37°C) induced a 7- to 31-fold increase in
blast cell attachment (211 ± 80 cells/field; n = 14). The adhesive
properties of L-selectin (CD62L), E-selectin (CD62E),  2-integrin
(CD18), and VCAM-1 (CD106) were then evaluated by studying the adhesion of blast cells in the presence of the adhesion blocking mAbs LAM1-3 (anti-CD62L), H18/7 (anti-CD62E), HAE-2 (anti-CD106), and TS1/18 (anti-CD18). The assay duration was 10 minutes to limit L-selectin shedding observed with longer durations. In this low shear stress assay
(approximately 0.7 dyne/cm2),37 blast cell
attachment to TNF--activated endothelium was found to be dependent
on L-selectin, E-selectin, 1 integrins, and 2-integrins (Table
2). Anti-L-selectin mAb LAM1-3 inhibited a major part of L-selectin+ blast cell attachment to
TNF--activated endothelium (50.7% ± 6.7%; n = 9;
P < .001, Table 2). In contrast, preincubation of L-selectin blast cells with LAM1-3 did not affect blast
cell attachment (data no shown). E-selectin supported blast cell
attachment of all blast cell suspensions that were tested and that
contributed to a major part of blast cell attachment
(57.0% ± 4.8%; n = 11; P < .001 Members of the
superfamily of immunoglobulins, VCAM-1 and ICAM-1, were also found to
support blast cell adhesion. Anti-VCAM-1 mAb HAE-2 inhibited blast
cell attachment from 8 patients with AML by 66.7% ± 7.7% and
anti-CD18 mAb TS1/18 by 49.0% ± 5.2% (n = 11). In 2 experiments,
the anti-PSGL-1 mAb KPL1 inhibited blast cell adhesion by 52% and
66%, indicating an important role for PSGL-1 in recruiting blast cells
at the surface of TNF--activated endothelium.
Myeloblasts progressively accumulate on unactivated endothelial cell monolayers Because little blast cell adhesion to unactivated endothelium was detectable at 10 minutes, the effect of longer incubation times was examined. Leukemic blasts were allowed to adhere to unactivated endothelial cells under static conditions at 37°C for 0.75, 3, 6, or 24 hours; endothelial cell monolayers were then washed gently and adherent cells were counted. With incubation times of up to 24 hours, there was a strong positive nonlinear correlation (R2 = 0.996) between blast cell adhesion at endothelial cell surface and incubation time (Figure 2). A possible explanation for this observation is that blast cells can activate endothelial cells, thereby inducing the expression of endothelial adhesion receptors such as ICAM-1, E-selectin, P-selectin, or VCAM-1.
Coculture of leukemic blast cells with unactivated endothelial cell monolayers induces endothelial E-selectin, P-selectin, ICAM-1, and VCAM-1 expression The ability of leukemic blasts to activate endothelial cells and to induce E-selectin, P-selectin, ICAM-1, and VCAM-1 expression was evaluated by coculturing blast cells with endothelial cell monolayers for 24 hours at 37°C. Immunostaining of endothelial cells with appropriate mAbs revealed the strong induction of ICAM-1, VCAM-1, E-selectin, and P-selectin expression but not of CD291 integrin or
CD31 (Table 3). At 24 hours, expression
levels of ICAM-1 (CD54) and VCAM-1 (CD106E) were higher than levels
seen for E-selectin (CD62E) or P-selectin (CD62P). VCAM-1 and
E-selectin expression were then determined at various times (0, 3, 6, and 24 hours of coculture). A progressive increase in VCAM-1 expression was detected over the 24-hour coculture period; in contrast, E-selectin expression peaked at 6 hours and decreased afterward (Figure
3). Importantly, in 2 experiments, the
coculture of human neutrophils with endothelial cells did not induce
the expression of P-selectin, E-selectin, and VCAM-1 and did not
increase ICAM-1 expression after 3 hours, 6 hours, and 24 hours of
coculture. These observations indicate that myeloblasts and neutrophils
have distinct behaviors that may strongly affect cell recruitment at
the endothelial cell surface.
Secretion by leukemic blast cells of factors inducing endothelial E-selectin, P-selectin, ICAM-1, and VCAM-1 expression Similar kinetics of E-selectin and VCAM-1 expression were observed when endothelial cells were cocultured with leukemic blast cells or when they were activated with 100 U/mL TNF- or 10 U/mL IL-1. This
observation suggests that activating cytokines might have been secreted
by leukemic blast cells during the coculture period. We tested this
hypothesis by culturing endothelial cell monolayers in the presence of
conditioned medium obtained from blast cell and endothelial cell
coculture. Strong expression of ICAM-1, VCAM-1, and E-selectin was
detectable when endothelial cell monolayers were incubated for 24 hours
at 37°C with conditioned medium obtained after 6 hours of coculture
of leukemic blasts with unactivated endothelium. ICAM-1 expression at
the surface of unactivated endothelial cells was 6% ± 1% and
43% ± 5% on endothelial cells exposed to coculture medium
(n = 13; P = .0013). VCAM-1 expression was not
detectable on unactivated endothelial cells and increased to
34% ± 6% on endothelial cells exposed to coculture medium
(n = 13; P = .0001). E-selectin expression was not
detectable on unactivated endothelial cells and 27% ± 5% on
endothelial cells exposed to coculture medium (n = 14;
P = .0001). The absence of VCAM-1 and E-selectin
expression on unactivated endothelial cells was
expected.14,38,39 Additional experiments were undertaken to test the possibility that endothelial cell receptor expression after
endothelium exposure to coculture medium was related to the presence of
endotoxin in conditioned medium. This possibility was rejected because
similar levels of ICAM-1, VCAM-1, and E-selectin expression were
observed using unprocessed coculture medium or coculture medium
adsorbed 3 times on an endotoxin-removing affinity-gel column. Finally,
the role of blast cell adhesion to endothelial cell monolayers in
inducing ICAM-1 and VCAM-1 expression at the endothelial cell surface
was examined by comparing the expression of these molecules after 20 hours of coculture of leukemic blast cells and endothelium in direct
contact or separated by a membrane with 0.4-µm pores. After 6 hours
of coculture at 37°C, weaker induction of ICAM-1 expression was
observed when leukemic blast cells were separated from endothelial cell
monolayers than when direct contact was allowed (67% ± 4% vs
77% ± 3%; n = 3; P = .007). A similar trend was
detectable for VCAM-1 expression (26% ± 16% vs
39% ± 11%;n = 2).
Prevention of endothelial cell activation by anticytokine antibodies Several studies have shown that myeloblasts can secrete TNF- or
IL-1. The involvement of these cytokines in coculture experiments presented here was evaluated using antibodies against TNF- or IL-1. Leukemic blast cell suspensions from 3 different patients (patient 1, M2 AML; patient 2, M0 AML; and patient 3, M4 AML) were
treated with anti-IL-1 or anti-TNF- antibodies. The effect of
anti-IL-1 treatment was examined using E-selectin and ICAM-1 expression as criteria. E-selectin expression was 31% on endothelial cells incubated for 4 hours with the culture medium of a blast cell
suspension (107 cells/mL) obtained from patient 1 with M2
AML (Figure 4A, lower left). In contrast,
E-selectin expression was only 1% when blast cell culture medium was
treated with anti-IL-1 (5 µg/mL) (Figure 4A, lower right). This
treatment also reduced ICAM-1 expression. Similarly, the expression of
ICAM-1 on endothelial cells was reduced from 38% in the presence of
untreated blast cell culture medium from patient 1 to 15% in the
presence of anti-IL-1-treated conditioned medium (not
illustrated). The effect of anti-TNF- treatment was examined in
subsequent experiments in which VCAM-1 and ICAM-1 expression were used
as endothelial cell activation criteria. VCAM-1 and ICAM-1 expression
were, respectively, 77% and 93% when endothelial cells were incubated
for 14 hours with the culture medium of blast cells (107
cells/mL) obtained from patient 2 with M0 AML. VCAM-1 and ICAM-1 expression were reduced to, respectively, 26% and 53% when blast cell
culture medium was treated with anti-TNF- (5 µg/mL) (not illustrated). Additional experiments were performed using a third culture medium prepared using a blast cell suspension from patient 3 with M4 AML. Anti-IL-1 treatment alone had only a weak effect in
preventing E-selectin endothelial cell expression by this culture medium. E-selectin expression was 83% with anti-IL-1-treated culture medium (Figure 4B, lower left) versus 95% with untreated culture medium (Figure 4B, upper right). A further small reduction in
E-selectin expression to 76% was seen when anti-TNF- antibody was
added to the anti-IL-1-treated culture medium (Figure 4B, lower
right). Thus, although the results obtained with the first 2 culture
media indicate that IL-1 and TNF- can play a key role in
promoting endothelial cell activation by blast cell supernatants, the
data obtained with the third supernatant indicate that additional mechanisms are also involved in this reaction.
Inhibition of leukemic blast cell-mediated endothelial cell activation by adhesion-blocking monoclonal antibodies Additional experiments were performed to evaluate the role of blast cell adhesion in inducing endothelial cell adhesion receptor expression. Leukemic blast cells (107/mL) were cultured on endothelial cell monolayers in the presence of adhesion-blocking mAbs directed against VCAM-1, ICAM-1, E-selectin, or P-selectin (mAb concentration, 10 µg/mL). After blast cell-endothelial cell monolayer coculture for 6 hours at 37°C, VCAM-1, ICAM-1, E-selectin, and P-selectin expression were assessed by endothelial cell immunostaining using FITC-labeled non-cross-blocking mAbs. Leukemic blast cell suspensions were obtained from patient 4 (M2 AML) and patient 5 (M5 AML). Adhesion-blocking mAbs G1 (anti-P-selectin) and HU 5/3 (anti-ICAM-1) partially prevented the induction of the expression of VCAM-1 and ICAM-1 on endothelial cell monolayers cultured in the presence of leukemic blasts from patient 4. VCAM-1 and ICAM-1 expression after 6 hours of coculture were, respectively, 25% and 60% in the absence of mAbs (Figure 5A, upper panels), 1% and 20% in the presence of the anti-P-selectin mAb G1 (Figure 5A, middle panels), and 1% and 26% in the presence of the anti-1 mAb HU 5/3 (Figure 5A, lower panels). However, ICAM-1 expression (55%) was not prevented by anti-VCAM-1 mAb HAE-2 (not illustrated). Similarly, ICAM-1 and VCAM-1 expression, which were 60% and 16% respectively, were not reduced by the presence of the anti-E-selectin mAb H18/7. The following pattern was observed with leukemic blasts from patient 5 with M5 AML. Anti-P-selectin mAb G1 and anti-ICAM-1 mAb HU 5/3 did not prevent VCAM-1 expression (not illustrated). However, anti-VCAM-1 mAb HAE-3 partially prevented E-selectin and ICAM-1 expression. Control experiments showed that E-selectin and ICAM-1 expression after 6 hours of blast cell-endothelial monolayer coculture were, respectively, 56% and 92% (Figure 5B, upper panels), 20% and 43% in presence of the anti-VCAM-1 mAb HAE-3 (Figure 5B, middle panels), and 50% and 68% in the presence of the anti-ICAM-1 mAb HU5/3 (Figure 5B, lower panels).
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. Observations made in this paper show that (1) the
expression of adhesion receptors among AML M0 to M5 FAB subtypes is
highly heterogeneous; (2) leukemic blast cell adhesion to
TNF- Immunophenotypic analysis showed that the expression of adhesion receptors by blast cells was heterogenous among the various AML subtypes. Moreover, as shown in Table 1, the expression of adhesion molecules also varied widely within each subtype. Statistical analysis did not disclose any relation between the expression of CD15, CD11a, CD18, CD49e, CD29, CD54, and the various AML subtypes. In contrast, higher levels of L-selectin expression were detected at the surface of M0 and M1 AML than on more differentiated M2, M3, M4 or M5 AML blast cells (Figure 1). Higher levels of CD49f, a receptor for laminin, were also observed on M0 AML and M1 AML blast cells, whereas M5 AML blasts did not express this receptor. The opposite was seen with CD11b, a receptor for ICAM-1, ICAM-2, C3b, fibrinogen, and factor X, as the highest levels of expression of CD11b were observed on myelomonoblastic leukemia M4 AML and monoblastic leukemia M5 AML blast cells. In agreement with earlier studies, lower levels of CD11b expression were found on M0, M1, M2, and M3 AML blast cells.45,46 These differences in adhesion receptor expression may affect myeloblast trafficking and patient prognosis.42,47 A study by the Eastern Cooperative Oncology Group suggested that CD11b+ AML may constitute a new leukemic syndrome with a poor response to chemotherapy and reduced survival.45 However, the impact of adhesion receptor expression on clinical presentation and response to therapy was not examined for the patients studied in this report. In future studies, correlations between the expression of these parameters and clinical presentation may be helpful to identify AML subgroups with unique trafficking behavior. As previously reported for normal leukocytes,7-11,14,48
myeloblast adhesion to TNF- Inflammatory cytokines and chemokines play a major role in regulating
leukocyte migration by inducing endothelial cell adhesion receptor
expression and by modulating the affinity of leukocyte integrins during
leukocyte rolling. As previously observed for normal
leukocytes,14 myeloblasts did not attach to endothelium in
a short-term (10-minute) nonstatic adhesion assay without prior endothelial cell activation by TNF- The possibility that factors secreted by blast cells could activate the
endothelium was suggested by observations showing that endothelial cell
exposure to supernatants of blast cell cultures induced E-selectin,
P-selectin, VCAM-1, and ICAM-1 expression and that the addition of
anti-TNF- In the experiment illustrated in Figure 4B, endothelial cell activation
by the cell culture supernatant was only partially inhibited by
anti-IL-1 Cell-cell contact generates intracellular signals that play an
important role in regulating cell growth, survival, and locomotion. Binding of L-selectin to its ligand, GlyCAM-1, or binding of P-selectin to PSGL-1 increases leukocyte integrin function. Along with chemotactic stimuli, these activating signals may regulate the transition from
leukocyte rolling to firm adhesion.69-73 Cross-talks
between Current models of leukocyte adhesion to vascular endothelium propose
that leukocytes roll on activated endothelial cells through selectins
and integrins.7,8 Integrin activation by chemokines and
selectins during rolling seems crucial for leukocyte arrest and firm
adhesion.13 We show here that myeloblasts use integrins and selectins to attach to cytokine-activated endothelium and that
blast cells can directly activate endothelial cells by secreting TNF-
Submitted July 31, 2000; accepted November 29, 2000.
Supported by grant KFS-499.8-1997 from the Swiss Cancer Research Foundation and grant 32-54069.98 from the Swiss National Foundation for Scientific Research.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Olivier Spertini, Division of Hematology, BH 18-543, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; e-mail: olivier.spertini{at}chuv.hospvd.ch.
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Top
Abstract
Introduction
including L-selectin, E-selectin, VCAM-1, and CD11/CD18
B, a pathway recently shown to be blocked by the arsenic compound
phenyl arsine oxide.