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

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.

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

Blood ◽

10.1182/blood.v46.4.495.495 ◽

1975 ◽

Vol 46 (4) ◽

pp. 495-507 ◽

Cited By ~ 66

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.

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

Blood ◽

10.1182/blood.v69.6.1570.bloodjournal6961570 ◽

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

Blood ◽

10.1182/blood.v46.4.495.bloodjournal464495 ◽

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.

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

Blood ◽

10.1182/blood.v68.4.967.967 ◽

1986 ◽

Vol 68 (4) ◽

pp. 967-970 ◽

Cited By ~ 25

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.

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Hairy cell leukemia: In-vitro proliferation and pseudo-colony formation

Leukemia Research ◽

10.1016/0145-2126(87)90137-8 ◽

1987 ◽

Vol 11 (10) ◽

pp. 911-921 ◽

Cited By ~ 3

Author(s):

J.C. Kluin-Nelemans ◽

H.W.J. Hakvoort ◽

J.T. van Dissel ◽

J.H. van Dierendonck ◽

G.C. Beverstock ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Colony Formation ◽

Hairy Cell ◽

Cell Leukemia ◽

In Vitro Proliferation

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BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

Blood ◽

10.1182/blood-2014-10-603100 ◽

2015 ◽

Vol 125 (8) ◽

pp. 1207-1216 ◽

Cited By ~ 43

Author(s):

Valentina Pettirossi ◽

Alessia Santi ◽

Elisa Imperi ◽

Guido Russo ◽

Alessandra Pucciarini ◽

...

Keyword(s):

B Cell ◽

Molecular Signature ◽

Hairy Cell ◽

Braf Inhibitors ◽

Cell Leukemia ◽

Antileukemic Activity ◽

Key Points ◽

Activating Mutation

Key Points The V600E kinase-activating mutation of BRAF profoundly shapes the distinct identity of HCL among B-cell neoplasms. Clinically available BRAF and MEK inhibitors exert potent antileukemic activity in patients’ HCL cells in vitro and in vivo.

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In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.598319 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alexia Vereertbrugghen ◽

Ana Colado ◽

Ernesto Gargiulo ◽

Raimundo Fernando Bezares ◽

Horacio Fernández Grecco ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Annexin V ◽

The Elderly ◽

Lymphocytic Leukemia ◽

Hairy Cell ◽

Cell Leukemia ◽

Current Standard ◽

Activated T Lymphocytes ◽

Low Incidence

Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.

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Soluble interleukin-2 receptors in the sera of patients with hairy cell leukemia: relationship with the effect of recombinant alpha-interferon therapy on clinical parameters and natural killer in vitro activity

Blood ◽

10.1182/blood.v70.5.1530.1530 ◽

1987 ◽

Vol 70 (5) ◽

pp. 1530-1535 ◽

Cited By ~ 72

Author(s):

M Chilosi ◽

G Semenzato ◽

G Cetto ◽

A Ambrosetti ◽

L Fiore-Donati ◽

...

Keyword(s):

Natural Killer ◽

Hairy Cell Leukemia ◽

Interleukin 2 ◽

Alpha Interferon ◽

Soluble Form ◽

Enzyme Linked Immunosorbent Assay ◽

Cell Mediated Immunity ◽

Hairy Cell ◽

Cell Leukemia

Abstract In this study we provide evidence that the sera of patients with hairy cell leukemia (HCL) contain a factor that can prevent the binding of a monoclonal antibody specific for interleukin-2 receptor (IL-2R) to its target. This factor corresponds to the soluble form of IL-2R (sIL-2R), as assessed by a specific enzyme-linked immunosorbent assay test, and appears to be released by neoplastic hairy cells. The serum sIL-2R levels were very high at diagnosis and significantly reduced during recombinant alpha-interferon (rIFN alpha 2) therapy. Values of sIL-2R appeared to be inversely related to the natural killer in vitro function displayed by peripheral blood mononuclear cells from the same patients. The presence of sIL-2R in the serum of patients with HCL might be involved in the impairment of cell-mediated immunity observed in these patients and could represent a valuable marker for monitoring different phases of the disease and for modulating IFN therapy.

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Host defense deficiency in hairy cell leukemia and its correction by leukocyte transfusion

Blood ◽

10.1182/blood.v56.3.526.526 ◽

1980 ◽

Vol 56 (3) ◽

pp. 526-533 ◽

Cited By ~ 14

Author(s):

EM Hersh ◽

S Murphy ◽

A Zander ◽

K Dicke ◽

DJ Stewart ◽

...

Keyword(s):

Host Defense ◽

Hairy Cell Leukemia ◽

Defense Mechanisms ◽

Pokeweed Mitogen ◽

Hairy Cell ◽

Cell Leukemia ◽

Con A ◽

Dependent Cell ◽

Monocyte Adherence

Abstract A similar defect host defense mechanisms in hairy cell leukemia was defined in two patients. Surface-adherent monocytes were not detected in the peripheral blood nor were monocytes that mediate antibody- dependent cell-mediated cytotoxicity (ADCC) to isoantibody-coated human erythrocytes. In addition, lymphocytes of both patients failed to show blastogenic responses to concanavalin A (Con-A) and pokeweed mitogen (PWM) but showed a vigorous response to phytohemagglutinin (PHA). Other immunologic abnormalities were present but were either moderate in degree or were not present in both patients. In vitro lymphocyte blastogenic responses were fully restored by incubation of patients' leukocytes with a normal donor's adherent monocytes. One patient received daily allogeneic leukocyte transfusion for 4 days. This resulted in complete normalization of monocyte adherence and ADCC that persisted for several months after transfusion and was associated with hemotalogic improvement. Therapy in case 1 resulted in correction of the blastogenic responses to Con-A and PWM. Thus, a host defense defect in hairy cell leukemia has been defined in 2 patients and a preliminary result suggests that therapy with leukocyte transfusions may be useful in the postsplenectomy patient with an infectious complication and should be explored further.

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