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 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 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 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 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 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

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 Hairy cell leukemia: a tumor of pre-plasma cells

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 620-629 ◽  
Author(s):  
KC Anderson ◽  
AW Boyd ◽  
DC Fisher ◽  
D Leslie ◽  
SF Schlossman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Plasma Cell ◽  
Hairy Cell Leukemia ◽  
Plasma Cells ◽  
Tartrate Resistant Acid Phosphatase ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Surface Antigens ◽  
Hairy Cells

Monoclonal antibodies defining B-, T-, and myeloid-restricted cell surface antigens were used to characterize the lineage and state of differentiation of tumor cells isolated from 22 patients with hairy cell leukemia (HCL). These tumors were shown to be of B lineage because they strongly expressed the B cell-restricted antigens B1 and B4 and lacked T cell- and monocyte-restricted antigens. Moreover, the strong expression of the plasma cell-associated PCA-1 antigen on the majority of hairy cells suggested that these tumors correspond to later stages of B cell ontogeny. Dual fluorescence experiments further confirmed that HCL splenocytes that coexpressed B1 and PCA-1 demonstrated both the morphology and tartrate-resistant acid phosphatase positivity of hairy cells. The observation that some hairy cells either spontaneously produce immunoglobulin (Ig) or could be induced to proliferate and secrete Ig provides complementary support for the view that HCL is a pre-plasma cell tumor. However, staining of hairy cells with anti-IL2R1 monoclonal antibody, which is directed to the T cell growth factor receptor and/or with the anti-Mo1 reagent, directed to C3bi complement receptor, distinguish these cells from currently identified B cells.

scholarly journals Monoclonal antibodies reactive with hairy cell leukemia [see comments]

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 320-325 ◽  
Author(s):  
L Visser ◽  
A Shaw ◽  
J Slupsky ◽  
H Vos ◽  
S Poppema
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Hairy Cell Leukemia ◽  
Small Population ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hairy Cells ◽  
A Minor ◽  
Insight Into

Monoclonal antibodies reactive with hairy cell leukemia were developed to aid in the diagnosis of this subtype of B cell chronic lymphocytic leukemia and to gain better insight into the origin of hairy cells. Three antibodies were found to be of value in the diagnosis of hairy cell leukemia. Antibody B-ly 2 can be considered a pan-B cell reagent and generally reacts similar to CD22 antibodies. Antibody B-ly 6 is reactive with the same antigen as CD11c (p150/95), an antigen that is present on hairy cell leukemia, macrophages, and a minor subpopulation of lymphocytes. Antibody B-ly 7 is a unique antibody reactive with 144 Kd antigen present only on hairy cell leukemia and a very small population of normal B lymphocytes. This subpopulation may be the counterpart of hairy cells.

scholarly journals Effective natural interferon-alpha therapy in recombinant interferon- alpha-resistant patients with hairy cell leukemia

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 38-43 ◽  
Author(s):  
P von Wussow ◽  
H Pralle ◽  
HK Hochkeppel ◽  
D Jakschies ◽  
S Sonnen ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Hairy Cell Leukemia ◽  
Mononuclear Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Recombinant Interferon ◽  
Homologous Protein ◽  
Ifn Alpha ◽  
Interferon Alpha Therapy ◽  
Alpha Therapy

Abstract To explore the relationship between anti-interferon-alpha (anti-IFN- alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha- 2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN- induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.

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