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 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 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.

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 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

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.

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 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.

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

Abstract 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.

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.

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