scholarly journals In vivo induction of proteins during therapy of hairy cell leukemia with alpha-interferon

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1570-1573 ◽  
Author(s):  
BL Samuels ◽  
HM Golomb ◽  
BH Brownstein
Keyword(s):  
Hairy Cell Leukemia ◽  
Polyacrylamide Gel Electrophoresis ◽  
Specific Protein ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Biochemical Effect ◽  
Ifn Alpha ◽  
Hairy Cells

Abstract The mechanism of the antineoplastic effect of interferon (IFN) is not known and may result from direct effects on the neoplastic cells themselves, activation of intermediary effector cells, or a combination of these effects. The synthesis of specific proteins is induced in hairy cells when they are exposed to alpha-IFN in vitro. In particular, the called p80, is markedly induced. We investigated this effect in the hairy cells of seven patients in the leukemic phase of hairy cell leukemia who were being treated with subcutaneous (SC) IFN alpha 2b (r- Hu-IFN-alpha 2). Polyacrylamide gel electrophoresis (PAGE) was carried out on [35S]methionine-labeled whole cell lysates visualized by autoradiography and silver staining. Within 2 days of starting IFN therapy, induction of specific protein synthesis, including p80 was seen by [35S]methionine labeling in freshly isolated circulating hairy cells from 6 of 6 patients tested. Therefore, alpha-IFN has a direct biochemical effect on hairy cells in vivo that is similar to in vitro effects, at least with regard to p80 synthesis, although the kinetics of this effect may vary in the two situations.

scholarly journals In vivo induction of proteins during therapy of hairy cell leukemia with alpha-interferon

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1570-1573
Author(s):  
BL Samuels ◽  
HM Golomb ◽  
BH Brownstein
Keyword(s):  
Hairy Cell Leukemia ◽  
Polyacrylamide Gel Electrophoresis ◽  
Specific Protein ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Biochemical Effect ◽  
Ifn Alpha ◽  
Hairy Cells

The mechanism of the antineoplastic effect of interferon (IFN) is not known and may result from direct effects on the neoplastic cells themselves, activation of intermediary effector cells, or a combination of these effects. The synthesis of specific proteins is induced in hairy cells when they are exposed to alpha-IFN in vitro. In particular, the called p80, is markedly induced. We investigated this effect in the hairy cells of seven patients in the leukemic phase of hairy cell leukemia who were being treated with subcutaneous (SC) IFN alpha 2b (r- Hu-IFN-alpha 2). Polyacrylamide gel electrophoresis (PAGE) was carried out on [35S]methionine-labeled whole cell lysates visualized by autoradiography and silver staining. Within 2 days of starting IFN therapy, induction of specific protein synthesis, including p80 was seen by [35S]methionine labeling in freshly isolated circulating hairy cells from 6 of 6 patients tested. Therefore, alpha-IFN has a direct biochemical effect on hairy cells in vivo that is similar to in vitro effects, at least with regard to p80 synthesis, although the kinetics of this effect may vary in the two situations.

scholarly journals Interferon-alpha downregulates the abnormal intracytoplasmic free calcium concentration of tumor cells in hairy cell leukemia

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2060-2065 ◽  
Author(s):  
E Genot ◽  
G Bismuth ◽  
L Degos ◽  
F Sigaux ◽  
J Wietzerbin
Keyword(s):  
Tumor Cell ◽  
B Cell ◽  
Hairy Cell Leukemia ◽  
Free Calcium ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ifn Alpha ◽  
Hairy Cells ◽  
Alpha Therapy

Abstract Hairy cell leukemia (HCL) is a B-cell tumor affecting the preplasma stage of B-cell differentiation. One important feature of the disease is its exquisite sensitivity to interferon-alpha (IFN-alpha) therapy. Because we showed earlier that the CD20 molecule is consistently hyperphosphorylated in hairy cells and because previous studies showed that CD20 is involved in regulating intracytoplasmic free calcium concentrations ([Ca2+]i) in normal B lymphocytes, we measured [Ca2+]i in tumor cell samples from patients with HCL and studied the effect of IFN-alpha on this parameter. Using the Ca(2+)-sensitive fluorophore fura-2, we observed that hairy cells display a slightly but consistently higher [Ca2+]i than normal 48-hour-activated B cells or other leukemic cells. Furthermore, both in vitro preincubation of cell samples with IFN-alpha and in vivo administration of this cytokine reduced the [Ca2+]i in hairy cells. This effect was observed together with a decrease in transmembrane Ca2+ influx. However, preincubation with IFN-gamma had no effect. The in vivo correlation between the diminution of CD20 phosphorylation and [Ca2+]i in tumor cell samples from patients at the beginning of IFN-alpha therapy suggests that these two parameters are connected.

scholarly journals Hairy cell leukemia: functional, immunologic, kinetic, and ultrastructural characterization

Blood ◽  
1975 ◽  
Vol 46 (4) ◽  
pp. 495-507 ◽  
Author(s):  
L Debusscher ◽  
JL Bernheim ◽  
E Collard-Ronge ◽  
A Govaerts ◽  
R Hooghe ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Phase Contrast ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ultrastructural Characterization ◽  
Contrast Microscopy ◽  
Hairy Cells

Abstract A diagnosis of hairy cell leukemia was made by optic microscopy, phase- contrast microscopy, electron microscopy, scanning microscopy, and histochemistry of the abnormal blood cells. In vivo these cells were found to have a half-time in the blood of approximately 150 hr. In vitro they had the capacity to adhere firmly to plastic, making it possible to obtain a pure population of hairy cells. Neither T-rosette formation nor phytohemagglutinin (PHA) transformation could be demonstrated in these cells. On the other hand, the presence of immunoglobulins on the surface of the hairy cells (HC) by immunofluorescence, and the synthesis and secretion by these cells of IgM type lambda-chains shown by radioimmunodiffusion, were in favor of their B-type lymphocyte origin. Similarities to chronic lymphocytic leukemia were apparent.

scholarly journals Interferon-alpha downregulates the abnormal intracytoplasmic free calcium concentration of tumor cells in hairy cell leukemia

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2060-2065
Author(s):  
E Genot ◽  
G Bismuth ◽  
L Degos ◽  
F Sigaux ◽  
J Wietzerbin
Keyword(s):  
Tumor Cell ◽  
B Cell ◽  
Hairy Cell Leukemia ◽  
Free Calcium ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ifn Alpha ◽  
Hairy Cells ◽  
Alpha Therapy

Hairy cell leukemia (HCL) is a B-cell tumor affecting the preplasma stage of B-cell differentiation. One important feature of the disease is its exquisite sensitivity to interferon-alpha (IFN-alpha) therapy. Because we showed earlier that the CD20 molecule is consistently hyperphosphorylated in hairy cells and because previous studies showed that CD20 is involved in regulating intracytoplasmic free calcium concentrations ([Ca2+]i) in normal B lymphocytes, we measured [Ca2+]i in tumor cell samples from patients with HCL and studied the effect of IFN-alpha on this parameter. Using the Ca(2+)-sensitive fluorophore fura-2, we observed that hairy cells display a slightly but consistently higher [Ca2+]i than normal 48-hour-activated B cells or other leukemic cells. Furthermore, both in vitro preincubation of cell samples with IFN-alpha and in vivo administration of this cytokine reduced the [Ca2+]i in hairy cells. This effect was observed together with a decrease in transmembrane Ca2+ influx. However, preincubation with IFN-gamma had no effect. The in vivo correlation between the diminution of CD20 phosphorylation and [Ca2+]i in tumor cell samples from patients at the beginning of IFN-alpha therapy suggests that these two parameters are connected.

scholarly journals Hairy cell leukemia: functional, immunologic, kinetic, and ultrastructural characterization

Blood ◽  
1975 ◽  
Vol 46 (4) ◽  
pp. 495-507
Author(s):  
L Debusscher ◽  
JL Bernheim ◽  
E Collard-Ronge ◽  
A Govaerts ◽  
R Hooghe ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Phase Contrast ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ultrastructural Characterization ◽  
Contrast Microscopy ◽  
Hairy Cells

A diagnosis of hairy cell leukemia was made by optic microscopy, phase- contrast microscopy, electron microscopy, scanning microscopy, and histochemistry of the abnormal blood cells. In vivo these cells were found to have a half-time in the blood of approximately 150 hr. In vitro they had the capacity to adhere firmly to plastic, making it possible to obtain a pure population of hairy cells. Neither T-rosette formation nor phytohemagglutinin (PHA) transformation could be demonstrated in these cells. On the other hand, the presence of immunoglobulins on the surface of the hairy cells (HC) by immunofluorescence, and the synthesis and secretion by these cells of IgM type lambda-chains shown by radioimmunodiffusion, were in favor of their B-type lymphocyte origin. Similarities to chronic lymphocytic leukemia were apparent.

scholarly journals Effect of interferon-alpha on the expression and release of the CD23 molecule in hairy cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2455-2463 ◽  
Author(s):  
E Genot ◽  
M Sarfati ◽  
F Sigaux ◽  
E Petit-Koskas ◽  
C Billard ◽  
...  
Keyword(s):  
Proliferative Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ifn Alpha ◽  
Hairy Cells ◽  
Alpha Therapy ◽  
Cd23 Expression ◽  
Cd23 Molecule

Abstract Hairy cells are stimulated to DNA synthesis by low molecular weight B cell growth factor (LMW-BCGF) and this proliferative response is suppressed by interferon (IFN)-alpha, both in vitro and in vivo. The suggestion that the CD23 molecule (Fc epsilon II receptor) might be involved in the signalling pathway of LMW-BCGF prompted us to study the expression of this molecule on hairy cells and its modulation by IFN- alpha. By flow cytometry and direct binding experiments with anti CD23 monoclonal antibodies, the presence of the CD23 antigen was detected in 7 of 12 cases tested, on variable percentages of cells, ranging from low to medium expression. In vitro incubation of hairy cells with IFN- alpha, which elicits a suppression of the proliferative response of these cells to LMW-BCGF, induced a parallel significant reduction of CD23 expression in only three cases. Similarly, a transient in vivo decrease of CD23 expression, concommitant with an inhibition of the LMW- BCGF response, could be detected in only one of three patients injected with IFN-alpha. Soluble sCD23/IgE-binding factor (BF) was quantitated in the serum from six other patients with hyperleukocytic hairy cell leukemia (HCL) undergoing a clinical trial of IFN-alpha therapy. Before treatment, these patients presented higher concentrations of the cleaved soluble form of the CD23 molecule than normal controls. Within a few weeks of IFN-alpha administration, these levels markedly decreased, paralleling a diminution of blood leukemic cells. Of interest, no such diminution was noticed for another patient resistant to IFN-alpha therapy. These results show that the proliferative response of hairy cells to LMW-BCGF is not linked to the expression of the CD23 marker. Besides, when the latter molecule was present, its decrease following IFN-alpha treatment, which could be detected in some cases, was not necessarily required for the suppression of the LMW-BCGF response and is thus not mandatory for the therapeutic efficacy of IFN- alpha. Our results point out that quantitation of serum sCD23/IgE-BF, whether related to a process of autocrine proliferation or not, is a parameter of potential importance for therapy monitoring.

scholarly journals Effect of interferon-alpha on the expression and release of the CD23 molecule in hairy cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2455-2463
Author(s):  
E Genot ◽  
M Sarfati ◽  
F Sigaux ◽  
E Petit-Koskas ◽  
C Billard ◽  
...  
Keyword(s):  
Proliferative Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Ifn Alpha ◽  
Hairy Cells ◽  
Alpha Therapy ◽  
Cd23 Expression ◽  
Cd23 Molecule

Hairy cells are stimulated to DNA synthesis by low molecular weight B cell growth factor (LMW-BCGF) and this proliferative response is suppressed by interferon (IFN)-alpha, both in vitro and in vivo. The suggestion that the CD23 molecule (Fc epsilon II receptor) might be involved in the signalling pathway of LMW-BCGF prompted us to study the expression of this molecule on hairy cells and its modulation by IFN- alpha. By flow cytometry and direct binding experiments with anti CD23 monoclonal antibodies, the presence of the CD23 antigen was detected in 7 of 12 cases tested, on variable percentages of cells, ranging from low to medium expression. In vitro incubation of hairy cells with IFN- alpha, which elicits a suppression of the proliferative response of these cells to LMW-BCGF, induced a parallel significant reduction of CD23 expression in only three cases. Similarly, a transient in vivo decrease of CD23 expression, concommitant with an inhibition of the LMW- BCGF response, could be detected in only one of three patients injected with IFN-alpha. Soluble sCD23/IgE-binding factor (BF) was quantitated in the serum from six other patients with hyperleukocytic hairy cell leukemia (HCL) undergoing a clinical trial of IFN-alpha therapy. Before treatment, these patients presented higher concentrations of the cleaved soluble form of the CD23 molecule than normal controls. Within a few weeks of IFN-alpha administration, these levels markedly decreased, paralleling a diminution of blood leukemic cells. Of interest, no such diminution was noticed for another patient resistant to IFN-alpha therapy. These results show that the proliferative response of hairy cells to LMW-BCGF is not linked to the expression of the CD23 marker. Besides, when the latter molecule was present, its decrease following IFN-alpha treatment, which could be detected in some cases, was not necessarily required for the suppression of the LMW-BCGF response and is thus not mandatory for the therapeutic efficacy of IFN- alpha. Our results point out that quantitation of serum sCD23/IgE-BF, whether related to a process of autocrine proliferation or not, is a parameter of potential importance for therapy monitoring.

scholarly journals c-myc and c-fos expression during interferon-alpha therapy for hairy cell leukemia

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 967-970 ◽  
Author(s):  
P Lehn ◽  
F Sigaux ◽  
D Grausz ◽  
P Loiseau ◽  
S Castaigne ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Hairy Cell Leukemia ◽  
Low Dose ◽  
Mrna Levels ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Prolymphocytic Leukemia ◽  
Ifn Alpha ◽  
Alpha Therapy

Abstract Low-dose interferon-alpha (IFN-alpha) therapy is consistently effective in the treatment of hairy cell leukemia (HCL). In two cases of resistance to IFN-alpha administration, we diagnosed variant HCL, a form of HCL with intermediate features between typical HCL and B cell prolymphocytic leukemia. We tried to distinguish variant and typical hairy cells (HCs) by Northern blot analysis of the oncogenes expressed in vivo. We report that variant HCs contain c-myc transcripts in contrast to typical HCs, whereas c-fos transcripts are detected in both cell types. We also report that the mRNA levels of c-myc are not modified in variant HCs by IFN-alpha treatment, whereas the level of c- fos mRNA is modulated in both types of HCs. Our findings suggest that the failure to modulate c-myc expression in vivo might indicate the limits of low-dose IFN-alpha therapy.

scholarly journals Induction of Apoptosis in Vivo and in Vitro in Hairy Cell Leukemia Treated by Deoxycoformycin

2000 ◽  
Vol 192 (1) ◽  
pp. 87-98
Author(s):  
Kazuei Ogawa ◽  
Tsutomu Shichishima ◽  
Naoya Nakamura ◽  
Yukio Maruyama
Keyword(s):  
Hairy Cell Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Induction Of Apoptosis

scholarly journals Mechanisms accounting for the defective natural killer activity in patients with hairy cell leukemia

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1525-1530
Author(s):  
L Trentin ◽  
R Zambello ◽  
C Agostini ◽  
A Ambrosetti ◽  
T Chisesi ◽  
...  
Keyword(s):  
Natural Killer ◽  
Target Cell ◽  
Hairy Cell Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Binding ◽  
Ifn Alpha ◽  
Binding Level ◽  
Alpha Therapy

Natural killer (NK) cell activity is severely impaired in untreated patients with hairy cell leukemia (HCL). In an attempt to investigate whether this impairment is related to a defect at the target cell binding and/or at the post target cell binding level, we evaluated the peripheral blood mononuclear cells (PBMC) of HCL patients for their ability to: (1) bind and kill K-562 NK-sensitive targets at the single cell binding level; (2) release the NK cytotoxic factor (NKCF) under different in vitro stimuli, including K-562 and phytohemoagglutinin; and (3) kill K-562 targets in a lectin-dependent cellular cytoxicity (LDCC) assay. This study demonstrates that untreated HCL patients' PBMC show a low ability to form conjugates with K-562 targets at the single cell binding level (5.7% +/- 1.0%) with respect to patients studied after treatment (9.3% +/- 1.3%) and controls (15.0% +/- 4.0%); P less than .05 and P less than .001, respectively. A decreased ability to kill the bound target was demonstrated in untreated cases (1.2% +/- 1.1%) versus patients studied after treatment and controls (12.3% +/- 1.6%, 17.0% +/- 3.1% respectively); P less than .001 in both conditions. After activation of effector cells with interleukin-2 (IL- 2) in vitro, an increase in the ability of PBMC to form conjugates with K-562 targets and kill the bound target was demonstrated in each group of patients. Moreover, IL-2 was able to increase the cytotoxicity against NK-sensitive targets in all patients tested. Evaluation of NKCF production showed that untreated patients release low levels of NKCF when PBMC were incubated in the presence of K-562 stimulators (1.8% +/- 0.7%) with respect to patients after interferon-alpha (IFN-alpha) therapy (7.6% +/- 2.1%) and controls (12.9% +/- 2.2%); P less than .02 and P less than .001, respectively. When the recognition mechanisms were bypassed by triggering the cells with lectins in an LDCC assay, we demonstrated an increase of the lytic activity in both groups of patients with respect to the baseline values. However, the cytotoxic capacity observed in untreated patients was significantly lower than that observed in subjects after IFN-alpha therapy and controls (P less than .001). These findings suggest that the impaired NK activity observed in patients with HCL is related to defects both at the target and posttarget cell binding levels.

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