A Novel Multiparameter Flow Cytometric Cytotoxicity Assay Detects p53 Deletion as the Major Cause of In Vitro Resistance to Fludarabine in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4470-4470
Author(s):  
James Z. Huang ◽  
Antony C. Bakke ◽  
Guang Fan ◽  
Rita Braziel ◽  
Ken M. Gatter ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Drug Exposure ◽  
Leukemic Cell ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Multiparameter Flow Cytometry ◽  
Diagnostic Strategy ◽  
Significant Difference

Abstract Individual patients with B-CLL demonstrate variable responses to standard induction and salvage therapeutic regimens. It would be highly desirable to develop a predictable and reproducible laboratory diagnostic strategy that guides the selection of appropriate drugs and/or regimens based on the drug sensitivity and resistance profiles of leukemic cells for individual patients. As a first step towards this goal, a study was designed to investigate the differences of in vitro drug sensitivity profiles of leukemic cells with different cytogenetic abnormalities from CLL patients. CLL cells from 43 patients were incubated in vitro with four commonly used chemotherapeutic agents (fludarabine, chlorambucil, cladribine or prednisolone) individually or in combination. Multiparameter flow cytometry was utilized to determine the decrease in leukemic cell viability after drug exposure. Both fresh and cryopreserved samples were assessed and were found to be equivalent for assay, regardless of the percentage of B-CLL cells or the degree of spontaneous apoptosis. The highest in vitro resistance to fludarabine, was seen in all seven cases of B-CLL cells with deletions of p53, a cytogenetic abnormality associated with poor clinical outcome. Interestingly, in vitro response to chlorambucil and prednisolone was seen some CLL cases with p53 deletion and correlated with clinical response to these drugs. In CLL cases without p53 deletion, a marked variability in vitro drug sensitivity CLL cells was observed but no significant difference was detected among cases with normal cytogenetics (n=13), ATM deletion (n=4), trisomy 12 (n=3), or 13q deletion (n=7). Our findings provide direct evidence of cellular resistance to fludarabine in CLL associated with p53 deletion, confirming prior clinical observations. In vitro drug sensitivity assay may prove useful in guiding choices for therapy for CLL patients based on the drug sensitivity profile of leukemic cells in individuals.

The Effects of the Macrocyclic Lactone Bryostatin-1 on Leukemic Cells in Vitro

1992 ◽  
Vol 78 (3) ◽  
pp. 167-171 ◽  
Author(s):  
Vittorio Gebbia ◽  
Pietro Citarrella ◽  
Vincenzo Miserendino ◽  
Roberto Valenza ◽  
Nicolò Borsellino ◽  
...  
Keyword(s):  
Macrocyclic Lactone ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Variable Degree ◽  
Monocytic Differentiation ◽  
Bryostatin 1 ◽  
Leukemic Cell Lines ◽  
Significant Difference

The macrocyclic lactone bryostatin-1 was found to exert in vitro antineoplastic activity against several leukemic cell lines, including human K562 erythroleukemia, HL60 promyelocytic leukemia, REH and MOLT-4 lymphoblastic leukemias, CCRFCEM lymphoma, KG-1 myeloid leukemia, and murine P388 lymphocytic leukemia. No statistically significant difference in sensitivity to bryostatin-1 was found between adriamycin-resistant P388 and K526 subclones and their sensitive counterparts. Freshly explanted clonogenic leukemic cells showed a variable sensitivity to bryostatin-1 in 10/12 tested samples. The IC50 of clonogenic leukemic cells was 4 × 10–3 M bryostatin-1, and that of normal marrow CFU-GM was 10–5 M. Leukemic cells exposed to bryostatin-1 showed a variable degree of monocytic differentiation as evaluated by ANAE staining and morphology. Bryostatin-1 is also able to inhibit the growth of CFU-GM from myelodysplastic marrow and to shorten the duration of dysplastic hematopoiesis in liquid culture. In conclusion, these data suggest that bryostatin-1 is a potent antileukemic agent in vitro that may be potentially useful for clinical studies.

Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2973-2979 ◽  
Author(s):  
Anne J. Novak ◽  
Richard J. Bram ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
B Lymphocyte Stimulator

B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.

Priming Effect with G-CSF Enhances In Vitro Apoptosis by Treatment with Ara-C and VP-16 in Leukemic Cell Line.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4333-4333
Author(s):  
Jun-ichi Kitagawa ◽  
Takeshi Hara ◽  
Hisashi Tsurumi ◽  
Nobuhiro Kanemura ◽  
Masahito Shimizu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Priming Effect ◽  
Low Dose ◽  
Combined Treatment ◽  
Annexin V ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Significant Difference

Abstract Introduction: We have recently reported that the effectiveness of low dose Ara-C, VP-16 and G-CSF (AVG therapy) for elderly AML patients who were ineligible for intensive chemotherapy (Hematol Oncol, in press). G-CSF has been reported to potentiate in vitro anti-leukemic effect of Ara-C. The mechanism of the potentiation is assumed to recruit quiescent G0 leukemic cells into cell cycle. We hypothesized that the enhanced cytotoxicity was due to the apoptosis by the effect of the priming of G-CSF, and the effect was depended on the cell cycle. In order to afford proof of this hypothesis, we assayed proliferation, apoptosis, and cell cycle in leukemic cell lines. Materials: Ara-C, VP-16, G-CSF was provided by Nippon Shinyaku, Nihonkayaku, Chugai pharmacy, respectively, Tokyo, Japan. 32D and HL-60 were obtained from RIKEN Bioresource Center Cell Bank (Ibaragi, Japan), Ba/F3 was generous gifts from Dr. Kume, Jichi medical school, Tochigi, Japan. Methods: 5 x 105/ml HL60, 32D and Ba/F3 were cultured with various concentrations of Ara-C and/or VP-16 in the presence or absence of G-CSF 50ng/ml for 3 days. At the end of the culture, cell proliferation and viability were determined by using the trypan blue. The Annexin V-binding capacity of treated cells was examined by flow cytometry using ANNEXIN V-FITC APOPTOSIS DETECTION KIT I purchased from BD Pharmingen™. Cell cycle analysis was done with BrdU Flow KIT purchased from BD Pharmingen™. The incorporated BrdU was stained with specific anti-BrdU fluorescent antibodies, and the levels of cell-associated BrdU are then measured by flow cytometory. Result: Ara-C and VP-16 inhibited proliferation and decreased viability of leukemic cell lines dose-dependently. Half killing concentration (IC50) was redused in combination of Ara-C and VP-16 than Ara-C or VP-16 alone. In G-CSF dependent cell line (32D), IC50 was redeced in the presence of G-CSF than absence of G-CSF at G-CSF, and there was no significant difference between with and without G-CSF in G-CSF independent cell lines (HL-60, Ba/F3) (p<0.05). In combined treatment of low dose Ara-C (10−7M) and VP-16 (10−7M), the percentage of apoptotic cells were increased to 20.67% from 13.04% by addition of G-CSF in 32D, and there was no significant differencebetween with and without G-CSF in HL-60 and Ba/F3 (p<0.05). At combined treatment of low dose Ara-C and VP-16, the percentage of G0/G1 phase cells were decreased to 43.94% from 35.63% and S phase cells were increased to 29.50% from 24.05% in 32D by addition of G-CSF, and there was no significant difference between with and without G-CSF in HL-60 and Ba/F3 (p<0.05). Discussion: We first showed a combination effect of Ara-C and VP-16. Next we demonstrated that the potentiation of the cytotoxicity was mediated through the mechanism of apoptosis, and apoptosis played an important role for eradicating leukemic cells by low dose Ara-C and VP-16. And G-CSF recruited cells G0/G1 phase into S phase in G-CSF dependent cells by addition of G-CSF. These results suggest that priming effect of G-CSF significantly potentiate the cytotoxicity mediated by AVG chemotherapy. Conclusion: The priming effect of G-CSF might be admitted at least of a part in AML cells.

scholarly journals Deoxyribonucleoside triphosphate accumulation by leukemic cells

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 419-424 ◽  
Author(s):  
BS Mitchell ◽  
NL Edwards ◽  
CA Koller
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adenosine Deaminase ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Culture Cells ◽  
Acute Nonlymphoblastic Leukemia ◽  
Deoxyribonucleoside Triphosphate

Abstract The toxicity of the deoxyribonucleosides, 2′-deoxyadenosine, 2′- deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5′-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5′-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2′- deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.

scholarly journals Biochemical correlates of the differential sensitivity of subtypes of human leukemia to deoxyadenosine and deoxycoformycin

Blood ◽  
1982 ◽  
Vol 60 (5) ◽  
pp. 1096-1102 ◽  
Author(s):  
SS Matsumoto ◽  
AL Yu ◽  
LC Bleeker ◽  
B Bakay ◽  
FH Kung ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Metabolic Response ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Differential Sensitivity ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Cell Leukemia

Abstract Leukemic cells incubated in vitro with 2′-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2′-deoxy-coformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD50, the concentration of dAdo that caused 50% inhibition of the incorporation of 3H-thymidine into cells in the presence of 20 microM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with 14C-dAdo plus DCF, a good correlation was observed between the LD50 and the ratio of 14C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The accumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto- ATPase, less well with cytoplasmic 5′-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5′-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.

The Valproic Acid-Fludarabine Combination Induces a Synergistic Response in Chronic Lymphocytic Leukemia Via a Mechanism Involving the Lysosomal Protease Cathepsin B.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2892-2892
Author(s):  
Ju-Yoon Yoon ◽  
David Szwajcer ◽  
Ganchimeg Ishdorj ◽  
Pat Benjaminson ◽  
James B Johnston ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cathepsin B ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Lysosomal Protease

Abstract Abstract 2892 Chronic Lymphocytic Leukemia (CLL) is the most common haematological malignancy in the western world. Fludarabine, a nucleoside analogue, is commonly used to treat Chronic Lymphocytic Leukemia (CLL) in untreated and relapsed CLL. However, patients commonly develop resistance to fludarabine. We hypothesize that the addition of Valproic Acid (VPA), an inhibitor of histone deacetylases (HDACs), can improve fludarabine-based therapy. The VPA-Fludarabine combination induced a synergistic response in human leukemic cells and primary CLL cells. Fludarabine also interacted synergistically with three other HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), Trichostatin A, and sodium butyrate, while the synergy was not observed with valpromide, the VPA analogue that does not inhibit HDACs. We confirmed that fludarabine treatment activates caspases-8, -9 and caspase-3, and we also show that fludarabine treatment activates caspase-2, an upstream caspase that has been implicated in cell death associated with lysosome membrane permeabilization (LMP). Activation of all four caspases was enhanced by the addition of VPA. Enhanced activation of caspases was associated with down-regulation of two prominent anti-apoptotic proteins, Mcl-1 and XIAP. The down-regulation of Mcl-1 and XIAP was dependent on the lysosomes, as their alkalinization using either chloroquine or NH4Cl partially stabilized both proteins, leading to reduced apoptosis. Chemical inhibition of a specific lysosomal protease, cathepsin B, using CA074-Me, was sufficient to stabilize Mcl-1 and XIAP, reduce caspase activation and apoptosis. Treatment with fludarabine or the VPA-fludarabine combination led to the loss of lysosome integrity, as visualized by fluorescent staining, thus suggesting a leakage of the lysosomal content into the cytosol in response to the drugs. Addition of purified cathepsin B to leukemic cell lysates led to the reduction in protein levels of Mcl-1, XIAP and pro-caspase-2, thus suggesting that the re-localization of cathepsin B into the cytosol is sufficient to drive cell death. VPA treatment enhanced cathepsin B levels in both leukemic cell lines and primary CLL cells. When cathepsin B activity was examined using zRR-AMC, a fluorogenic substrate of cathepsin B, VPA also increased cathepsin B activity, and this activity was abolished by the addition of CA074-Me. In parallel with the in vitro/ex vivo experiments, we had launched a phase II clinical trial at CancerCare Manitoba. Six relapsed CLL patients who had received at least one prior therapy with fludarabine were examined. No responses were seen after 28 days using VPA alone, in line with the in vitro observation of minimal cytotoxicity of VPA at low doses. However, in five patients who continued on VPA with fludarabine, three patients showed a >50% fall in lymphocyte/lymph node size after receiving five cycles of the combination. When the leukemic cells from VPA-treated CLL patients were examined, VPA administration induced increased levels of histone-3 acetylation and cathepsin B in vivo. In summary, a novel mechanism for fludarabine cytotoxicity has been elucidated, where fludarabine induces a loss of lysosomal integrity, leading to cathepsin B-dependent cell death. VPA interacted with fludarabine synergistically, and this synergy was associated with the VPA-induced increase in VPA level and activity. VPA induced increase in histone-3 acetylation and cathepsin B in vivo, and this induction of cathepsin B is likely to be contributing to the clinical response observed in fludarabine-relapsed/refractory CLL patients. Disclosures: Off Label Use: Valproic acid as adjunct therapy in Chronic Lymphocytic Leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Deoxyribonucleoside triphosphate accumulation by leukemic cells

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 419-424
Author(s):  
BS Mitchell ◽  
NL Edwards ◽  
CA Koller
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adenosine Deaminase ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Culture Cells ◽  
Acute Nonlymphoblastic Leukemia ◽  
Deoxyribonucleoside Triphosphate

The toxicity of the deoxyribonucleosides, 2′-deoxyadenosine, 2′- deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5′-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5′-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2′- deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.

scholarly journals Biochemical correlates of the differential sensitivity of subtypes of human leukemia to deoxyadenosine and deoxycoformycin

Blood ◽  
1982 ◽  
Vol 60 (5) ◽  
pp. 1096-1102 ◽  
Author(s):  
SS Matsumoto ◽  
AL Yu ◽  
LC Bleeker ◽  
B Bakay ◽  
FH Kung ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Metabolic Response ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Differential Sensitivity ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Cell Leukemia

Leukemic cells incubated in vitro with 2′-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2′-deoxy-coformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD50, the concentration of dAdo that caused 50% inhibition of the incorporation of 3H-thymidine into cells in the presence of 20 microM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with 14C-dAdo plus DCF, a good correlation was observed between the LD50 and the ratio of 14C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The accumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto- ATPase, less well with cytoplasmic 5′-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5′-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.

scholarly journals B-Chronic Lymphocytic Leukemia Autophagyc Cell Death by the Use of Manganese Doped Zinc Oxide Nanoparticles and Photo-Dynamic Therapy.

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Peña Sandra ◽  
Marín H. ◽  
Rodríguez Felipe ◽  
Dreon Marcos ◽  
Roque Gustavo ◽  
...  
Keyword(s):  
Zinc Oxide ◽  
Chronic Lymphocytic Leukemia ◽  
B Lymphocytes ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Zno Nps ◽  
Genetic Abnormalities ◽  
Novel Method

B-Chronic Lymphocytic Leukemia (B-CLL) usually follows an adverse, relentless clinical course by slowly developing drug resistance to fludarabine and other chemotherapeutic agents, as well as by acquiring new different genetic abnormalities. As B-CLL cells spontaneously produce high amounts of Reactive Oxygen Species (ROS) having an altered redox state in relation to that of normal B lymphocytes, we decided to probe different metal Zinc nanoparticles (ZnNPs) and quantify the levels of Singlet Oxigen (SO) to see if variations of its intracellular concentrations could execute and accelerate deadly programs in leukemic cells rather than in normal B lymphocytes, when applied with Photodynamic Therapy (PDT). In this way, we developed and tested a variety of metal ZnNPs of which one made of 0.5% Manganese Doped Zinc Oxide (ZnO:Mn) was finally selected for further testing as it had the best fludarabine resistant B-CLL cells in vitro killing activity, specially when combined with PDT. An interesting and rapidly dying process of B-CLL cells, known as autophagy, was always seen under Transmission Electronic Microscopy (TEM) when incubated with these 0.5% Mn doped ZnO NPs. This phenomenon correlated well with those intracellular increases of SO when PDT was administered, and measured by a novel method first described by us. As this therapy seems to be very specific to fludarabine resistant B-CLL cells, producing almost no damage to normal lymphocytes, it could surely contribute in the near future as a new innovative targeted strategy to be delivered in the clinical setting for the definitive benefit of these bad prognostic patients.

scholarly journals IL-10 Rescues CLL Survival through Repolarization of Inflammatory Nurse-like Cells

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 16
Author(s):  
Marcin Domagala ◽  
Loïc Ysebaert ◽  
Laetitia Ligat ◽  
Frederic Lopez ◽  
Jean-Jacques Fournié ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Elevated Level ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Soluble Factors ◽  
High Viability ◽  
Blocking Antibodies ◽  
Molecular Balance

Tumor-associated macrophages (TAMs) in chronic lymphocytic leukemia (CLL) are also called nurse-like cells (NLC), and confer survival signals through the release of soluble factors and cellular contacts. While in most patient samples the presence of NLC in co-cultures guarantees high viability of leukemic cells in vitro, in some cases this protective effect is absent. These macrophages are characterized by an “M1-like phenotype”. We show here that their reprogramming towards an M2-like phenotype (tumor-supportive) with IL-10 leads to an increase in leukemic cell survival. Inflammatory cytokines, such as TNF, are also able to depolarize M2-type protective NLC (decreasing CLL cell viability), an effect which is countered by IL-10 or blocking antibodies. Interestingly, both IL-10 and TNF are implied in the pathophysiology of CLL and their elevated level is associated with bad prognosis. We propose that the molecular balance between these two cytokines in CLL niches plays an important role in the maintenance of the protective phenotype of NLCs, and therefore in the survival of CLL cells.

Sign in / Sign up

Export Citation Format

Share Document