The Novel Sequence-Specific DNA Cross-Linking Agent SJG-136 (NSC 694501) Has Potent and Selective In vitro Cytotoxicity in Human B-Cell Chronic Lymphocytic Leukemia Cells with Evidence of a p53-Independent Mechanism of Cell Kill

Abstract During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL- 5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.

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Enhancement of antigen presentation of human B-cell chronic lymphocytic leukemia cells treated with phorbol ester 12-0-tetradecanoylphorbol-13-acetate.

Japanese Journal of Clinical Immunology ◽

10.2177/jsci.13.253 ◽

1990 ◽

Vol 13 (3) ◽

pp. 253-267

Author(s):

Tomoo Shiroguchi

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Antigen Presentation ◽

Phorbol Ester ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cell Chronic Lymphocytic Leukemia ◽

Human B Cell

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Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bcl-2 expression and is inhibited by IL-4

Blood ◽

10.1182/blood.v84.7.2297.bloodjournal8472297 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2297-2304 ◽

Cited By ~ 2

Author(s):

T Mainou-Fowler ◽

VA Craig ◽

JA Copplestone ◽

MD Hamon ◽

AG Prentice

Keyword(s):

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Percentage Increase ◽

Spontaneous Apoptosis ◽

Interleukin 5 ◽

The Third ◽

The Mean ◽

Induced Apoptosis ◽

Cell Chronic Lymphocytic Leukemia

During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL- 5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.

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Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD

Blood ◽

10.1182/blood.v95.4.1199.004k21_1199_1206 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1199-1206 ◽

Cited By ~ 59

Author(s):

Simona Zupo ◽

Rosanna Massara ◽

Mariella Dono ◽

Edoardo Rossi ◽

Fabio Malavasi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Plasma Cells ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cross Linking ◽

Malignant Cells ◽

Kinase Phosphorylation ◽

Δ Chain ◽

Effect Of Surface

Previously, we demonstrated that B-chronic lymphocytic leukemia (B-CLL) cells could be divided into 2 groups depending on the expression of CD38 by the malignant cells. The 2 groups differed in their signal-transducing capacities initiated by cross-linking of surface IgM; only in CD38-positive cells was an efficient signal delivered, invariably resulting in cell apoptosis. In this study, we investigated the effect of surface IgD cross-linking in 10 patients with CD38-positive B-CLL. Exposure of the malignant cells to goat antihuman δ-chain antibodies (Gaδ-ab) caused [Ca++]i mobilization and tyrosine kinase phosphorylation in a manner not different from that observed after goat antihuman μ-chain antibody (Gaμ-ab) treatment in vitro. However, Gaδ-ab-treated cells failed to undergo apoptosis and instead displayed prolonged survival in culture and differentiated into plasma cells when rIL2 was concomitantly present. Cross-linking of surface IgD failed to induce proliferation of the malignant cells in vitro. Moreover, treatment with Gaδ-ab did not prevent apoptosis of B-CLL cells induced by Gaμ-ab. Collectively, these experiments demonstrated that IgM and IgD expressed by the same cell may deliver opposite signals under particular circumstances and provide some clues for the understanding of the pathophysiology of B-CLL.

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