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

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.

scholarly journals Cytoskeleton organization is aberrantly rearranged in the cells of B chronic lymphocytic leukemia and hairy cell leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 233-239 ◽  
Author(s):  
F Caligaris-Cappio ◽  
L Bergui ◽  
L Tesio ◽  
G Corbascio ◽  
F Tousco ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Hairy Cell Leukemia ◽  
Close Contact ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Adhesive Properties

Abstract The organization of actin-containing microfilaments and vimentin- containing intermediate filaments has been investigated in B chronic lymphocytic leukemia (B-CLL), hairy cell leukemia (HCL), and normal B cells cultured in vitro under basal conditions and after induction with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). In uninduced B-CLL cells, F-actin was predominantly associated with dot-shaped structures scattered over the ventral membrane representing spotty close contact adhesion sites analogous to ““podosomes” described in other cell types. On TPA induction, podosomes became clustered in sharply defined areas sitting in the cell center beneath the nucleus. In some cells, long actin-containing protrusions appeared. In HCL cells, F-actin was associated with thin microvilli responsible for the “hairy” appearance; occasional cells showed scattered podosomes. On TPA induction, HCL cells sprouted long dendritic processes rich in submembraneous F-actin, which made intertwined networks. Therefore, in both B-CLL and HCL cells, adhesion structures were present and the capacity for adhesion in vitro was marked, which might explain some peculiar clinical features of the diseases. Adhesion structures and adhesive properties never appeared in normal B cells. These data further support the notion that B-CLL and HCL, although clinically different, may share common biological features and suggest that in these disorders, cytoskeleton modifications may represent a hallmark of transformation.

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.

In-vitro induction of some features of hairy cell leukemia in chronic lymphocytic leukemia and immunocytoma cells

1985 ◽  
Vol 50 (1) ◽  
pp. 29-31 ◽  
Author(s):  
H. W. L. Ziegler-Heitbrock ◽  
B. D�rken ◽  
R. Munker ◽  
G. Riethm�ller ◽  
S. Thierfelder ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hairy Cell Leukemia ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
In Vitro Induction

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 Cytoskeleton organization is aberrantly rearranged in the cells of B chronic lymphocytic leukemia and hairy cell leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 233-239 ◽  
Author(s):  
F Caligaris-Cappio ◽  
L Bergui ◽  
L Tesio ◽  
G Corbascio ◽  
F Tousco ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Hairy Cell Leukemia ◽  
Close Contact ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Adhesive Properties

The organization of actin-containing microfilaments and vimentin- containing intermediate filaments has been investigated in B chronic lymphocytic leukemia (B-CLL), hairy cell leukemia (HCL), and normal B cells cultured in vitro under basal conditions and after induction with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). In uninduced B-CLL cells, F-actin was predominantly associated with dot-shaped structures scattered over the ventral membrane representing spotty close contact adhesion sites analogous to ““podosomes” described in other cell types. On TPA induction, podosomes became clustered in sharply defined areas sitting in the cell center beneath the nucleus. In some cells, long actin-containing protrusions appeared. In HCL cells, F-actin was associated with thin microvilli responsible for the “hairy” appearance; occasional cells showed scattered podosomes. On TPA induction, HCL cells sprouted long dendritic processes rich in submembraneous F-actin, which made intertwined networks. Therefore, in both B-CLL and HCL cells, adhesion structures were present and the capacity for adhesion in vitro was marked, which might explain some peculiar clinical features of the diseases. Adhesion structures and adhesive properties never appeared in normal B cells. These data further support the notion that B-CLL and HCL, although clinically different, may share common biological features and suggest that in these disorders, cytoskeleton modifications may represent a hallmark of transformation.

scholarly journals Cell markers in hairy cell leukemia studied in cells from 51 patients

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 52-60 ◽  
Author(s):  
J Jansen ◽  
HR Schuit ◽  
CJ Meijer ◽  
JA van Nieuwkoop ◽  
W Hijmans
Keyword(s):  
Heavy Chain ◽  
Hairy Cell Leukemia ◽  
Lymphocytic Leukemia ◽  
Mature Stage ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Neoplastic Cells ◽  
Hairy Cells ◽  
Immunoglobulin Levels ◽  
Chain Type

Abstract To determine the maturation arrest of the neoplastic cells of hairy- cell leukemia (HCL) and the spectrum of the surface markers on these cells, a series of 51 patients with this disease was studied. The cells of all but two of the patients showed monoclonal surface Ig with respect to light chains. In about one-third of the cases, only gamma heavy chain determinants were present on the cells; the majority carried multiple heavy chain determinants as documented by the application of different fluorochromes. Two patients each showed two different clones of cells, both of the same light chain type. In one of these two patients, two paraproteins were present in the serum. Intracytoplasmic Ig was found in only 4 of 39 cases, in all instances being IgM. All cases studied concerned cells with FclgG receptors; however, the density of this receptor varied. FcIgM receptors also showed a spectrum of density, with some cases showing very few FcIgM- positive cells. Receptors C3 were not observed on the hairy cells. Serum immunoglobulin levels were normal or increased. Paraproteins were found in the sera of 4 of 38 patients. These data suggest that HCL is a neoplasm of B lymphocytes. The neoplastic cells are probably arrested at a more mature stage than the cells of chronic lymphocytic leukemia. The multiple isotypes on the cells indicate a block at the “switch” phase from the small micro-carrying lymphocyte to the larger Ig- producing lymphocyte or plasma cell.

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 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 Inhibition against CFU-C and CFU-E colony formation by soluble factor(s) derived from hairy cells

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 907-913 ◽  
Author(s):  
N Taniguchi ◽  
H Kuratsune ◽  
A Kanamaru ◽  
Y Tokumine ◽  
S Tagawa ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Colony Formation ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hairy Cells ◽  
Cell Conditioned Medium ◽  
Normal Controls

Abstract The inhibitory effect by hairy cell conditioned medium (HCCM) on the growth of granulocyte and erythrocyte colony forming cells was studied in vitro. The percent inhibition of CFU-C formation by HCCM from four hairy cell leukemia (HCL) patients ranged from 36% to 76%, while no inhibition was observed with conditioned medium (CM) obtained from three B-cell chronic lymphocytic leukemia (B-CLL) patients nor from two normal controls. HCCM inhibited specially the growth of rG-CSF responding stem cells. The hairy cell-derived colony inhibitory factor from HCCM was nondialyzable, fairly stable to heat treatment, and trypsin sensitive. Its maximal inhibitory activity against granulopoiesis was observed in the fractions of 5,000 to 6,000 daltons. Moreover HCCM inhibited CFU-E colony formation but not BFU-E. These results indicate that hairy cells produce a factor that inhibits granulopoiesis and erythropoiesis in vitro. This factor may play a role in neutropenia and anemia observed in HCL.

Involvement of CD44-hyaluronan interaction in malignant cell homing and fibronectin synthesis in hairy cell leukemia

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3161-3167 ◽  
Author(s):  
Khalil A. Aziz ◽  
Kathleen J. Till ◽  
Mirko Zuzel ◽  
John C. Cawley
Keyword(s):  
Hairy Cell Leukemia ◽  
Actin Polymerization ◽  
Malignant Cell ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Spontaneous Movement ◽  
Cell Adhesion And Migration ◽  
Cell Arrest ◽  
Hepatic Portal

Abstract The tissue homing of malignant hematic cells has both diagnostic and pathogenetic importance. Although such homing is incompletely understood, it generally involves cell adhesion and migration mediated by a number of adhesion receptors and cytokines. In this article, the potential importance of hyaluronan (HA) is examined for the tissue homing of hairy cells (HCs) in hairy cell leukemia (HCL). It is shown that HCs readily adhere to, and spontaneously move on, HA-coated surfaces using CD44. This indicates that activated CD44 and spontaneous movement on HA form part of the intrinsically activated phenotype of HCs. Interleukin-8 (IL-8) inhibited HC movement on HA, and this cell arrest was accompanied by increased actin polymerization and a more pronounced association of CD44 with the cytoskeleton. All of these findings are in sharp contrast to our previous observations with chronic lymphocytic leukemia cells, which are nonmotile on HA, but in response to IL-8 become polarized and motile using the receptor for HA-mediated motility rather than their apparently inactive CD44. Immunohistochemical examination of HCL tissues showed the ubiquitous presence of IL-8 and the prominence of HA in bone marrow stroma and hepatic portal tracts. This suggests that CD44-HA interactions are important in HC homing to these sites, but not to splenic red pulp or hepatic sinusoids, where HA is largely absent. Moreover, engagement of CD44 on HCs stimulates fibronectin synthesis, an observation that is likely to be relevant to the restriction of fibrosis in the disease to HC-infiltrated areas containing HA.

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