scholarly journals Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2423
Author(s):  
Jacopo Albanesi ◽  
Nelida Ines Noguera ◽  
Cristina Banella ◽  
Tommaso Colangelo ◽  
Elisabetta De Marinis ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Promyelocytic Leukemia ◽  
Metabolic Reprogramming ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.

scholarly journals Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1939-1950 ◽  
Author(s):  
L Benedetti ◽  
F Grignani ◽  
BM Scicchitano ◽  
AM Jetten ◽  
D Diverio ◽  
...  
Keyword(s):  
Cell Line ◽  
Signaling Pathway ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Type Ii ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha- selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha- dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

scholarly journals Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1939-1950 ◽  
Author(s):  
L Benedetti ◽  
F Grignani ◽  
BM Scicchitano ◽  
AM Jetten ◽  
D Diverio ◽  
...  
Keyword(s):  
Cell Line ◽  
Signaling Pathway ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Type Ii ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

Abstract All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha- selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha- dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

scholarly journals Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin ofCASPASE-10in Acute Promyelocytic Leukemia Cells

2002 ◽  
Vol 277 (51) ◽  
pp. 49504-49510 ◽  
Author(s):  
Ji Li ◽  
Peili Chen ◽  
Natasha Sinogeeva ◽  
Myriam Gorospe ◽  
Robert P. Wersto ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Promyelocytic Leukemia ◽  
Therapeutic Effects ◽  
Acid Therapy ◽  
Nb4 Cells

Arsenic trioxide (As2O3) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As2O3is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In this report, using cDNA arrays, we have examined the changes in gene expression profiles triggered by clinically achievable doses of As2O3in acute promyelocytic leukemia NB4 cells.CASPASE-10expression was found to be potently induced by As2O3. Accordingly, caspase-10 activity also substantially increased in response to As2O3treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As2O3-triggered apoptosis. Interestingly, the treatment of NB4 cells with As2O3markedly increased histone H3 phosphorylation at serine 10, an event that is associated with acetylation of the lysine 14 residue. Chromatin immunoprecipitation assays revealed that As2O3potently enhances histone H3 phosphoacetylation at theCASPASE-10locus. These results suggest that the effect of As2O3on histone H3 phosphoacetylation at theCASPASE-10gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.

scholarly journals Retinoic acid is required for and potentiates differentiation of acute promyelocytic leukemia cells by nonretinoid agents

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2122-2129 ◽  
Author(s):  
A Chen ◽  
JD Licht ◽  
Y Wu ◽  
N Hellinger ◽  
W Scher ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Acute Promyelocytic Leukemia ◽  
Drug Exposure ◽  
Primary Cultures ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Line ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

Abstract Patients with acute promyelocytic leukemia (APL) associated with the t(15;17) translocation and fusion of the promyelocytic leukemia (PML) and retinoic acid receptor-alpha (RAR-alpha) genes achieve complete remission but not cure with all-trans retinoic acid (RA), NB4, a cell line derived from a patient with t(15;17) APL that undergoes granulocytic differentiation when treated with pharmacologic doses of RA, was used as a model for differentiation therapy of APL. We found that NB4 cells are resistant to differentiation by nonretinoid inducers such as hexamethylene bisacetamide (HMBA), butyrates, vitamin D3, or hypoxanthine, all of which can induce differentiation in the commonly used HL60 leukemia cell line. Preexposure of NB4 cells to low concentrations of RA for a period as short as 30 minutes abolished resistance to nonretinoids and potentiated differentiation. Sequential RA and HMBA treatment yielded maximal differentiation by 3 days of drug exposure, whereas the effect of RA alone peaked after 6 days and yielded a smaller percentage of differentiated cells. RA also reversed NB4 cell resistance to butyrates and allowed for synergistic differentiation by these agents. Pretreatment with HMBA before exposure to RA failed to stimulate differentiation. Sequential RA/HMBA treatment also markedly increased the extent of differentiation of primary cultures of bone marrow and peripheral blood mononuclear cells from three APL patients. In one case RA/HMBA treatment overcame resistance to RA in vitro. Together, these results suggest that intermittent low doses of RA followed by either HMBA or butyrates may be a useful combination in the treatment of APL. This clinical strategy may help prevent or overcome RA resistance in APL.

Death Associated Protein 5 (DAP5/p97/NAT1) Contributes to Retinoic Acid-Induced Granulocytic Differentiation and Arsenic Trioxide Induced Apotosis through Inhibition of PI3K/Akt/mTOR Pathway in Acute Promyelocytic Leukemia Cells: A Novel Mechanism.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2836-2836
Author(s):  
Bulent Ozpolat ◽  
Ugur Akar ◽  
Isabel Zorilla-Calancha ◽  
Pablo Vivas-Mejia ◽  
Gabriel Lopez-Berestein
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Translation Initiation ◽  
Promyelocytic Leukemia ◽  
Mtor Pathway ◽  
Granulocytic Differentiation ◽  
Induced Expression ◽  
Nb4 Cells ◽  
Induced Apoptosis

Abstract All-trans Retinoic Acid (ATRA) is a naturally occurring metabolite of retinol (vitamin A)and acts as a potent inducer of cellular differentiation and growth arrest in acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (M3-AML). APL is characterized by translocation t(15;17), fusing PML (promyelocytic leukemia) and RARα (retinoic acid receptor) genes, leding to expression of PML/RARα receptor protein and differentiation block. Arsenic trioxide (ATO) induces (<0.5 μM) differentiation at low doses and apoptosis at high doses (>1 μM) in APL cells. Currently, both ATRA and ATO are successfully used in the treatment of APL in the clinic. However, the molecular mechanisms of myeloid differentiation and apoptosis induced by these agents are not fully understood. We previously reported that ATRA inhibits the translation initiation through multiple mechanisms, including upregulation of translation initiation inhibitors, DAP5/p97 and PDCD4 tumor suppressor protein. Here we investigated the role and regulation of death associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in myeloid (granulocytic and monocytic) cell differentiation and apoptosis. We found that ATRA (1 μM) induced a marked DAP5/p97 protein and mRNA expression during granulocytic differentiation of NB4 and HL60 cells but not in differentiation-resistant cells, which express very low levels of DAP5/p97. DAP5/p97 was translocated into nucleus during the differentiation of NB4 cells induced ATRA. At differentiation inducing doses, ATO, dimethysulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate-13-acetate also induced a significant DAP5/p97 expression in NB4 cells. However, ATO at apoptotic doses, but not ATRA, induced DAP5/p86, a proapoptotic form of DAP5/p97. ATRA and ATO -induced expression of DAP5/p97 was associated with inhibition of phosphaditylinositol 3-kinase (PI3K)/Akt pathway, which is known to stimulate cap-dependent translation of mRNAs. To show direct link between PI3K/Akt/mTOR pathway and DAP5 expression, we treated cell with PI3K and mTOR inhibitors LY294002 and by rapamycin, respectively. We found that inhibition of PI3K/Akt/mTOR pathway upregulated DAP5/p97 expression in NB4 cells. Finally, knockdown of DAP5/p97 expression by small interfering RNA significantly inhibited ATRA-induced granulocytic differentiation detected by expression of CD11b and ATO-induced apoptosis in NB4 cells detected by Annexin V assay (p<0.05). In conclusion, our data suggest that DAP5/p97 plays a role in ATRA-induced differentiation and ATO-induced apoptosis in APL cells. Our data demonstrated for the first time that DAP5/p97 is constitutively suppressed by of PI3K/Akt/mTOR pathway, and ATRA and ATO-induced expression of DAP5 is mediated by the inhibition of this survival pathway, suggesting a novel mechanism of DAP5 regulation and a role of translational control in induction of differentiation and apoptosis. Figure Figure

scholarly journals The PML/RARα-Regulated MiR-181a/b-Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2195-2195
Author(s):  
Daniela Braeuer-Hartmann ◽  
Jens-Uwe Hartmann ◽  
Dennis Gerloff ◽  
Christiane Katzerke ◽  
Alexander Arthur Wurm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Suppressor ◽  
Acute Promyelocytic Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Granulocytic Differentiation ◽  
Nb4 Cells ◽  
Knock Down ◽  
Functional Studies

Abstract In acute promyelocytic leukemia (APL) bearing the translocation t(15;17), all-trans-retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. Several factors are involved in the formation of the leukemic phenotype. Latest studies identified microRNAs as critical players in this network. In a micro array based microRNA screen we could identify the genomically clustered miR-181a and miR-181b as downregulated in the APL cell line NB4 by treatment with pharmacological doses of ATRA. In addition, the expression of the miR-181a/b-cluster was strongly reduced in bone marrow samples of APL patient while ATRA-based therapy. Furthermore, we showed the transcriptional induction of miR-181a and miR-181b by the APL-associated PML-RARα oncogene in vitro and in vivo. In PR9 cells, carrying a zinc-driven PML/RARα construct, and in PML/RARα-knock in mice the expression of the fusion gene leads to upregulation of the microRNA-cluster expression. Analysis of bone marrow samples of APL patients showed an enhanced expression of miR-181a and miR-181b in comparison to AML patient samples with normal karyotype, whereas other AML subgroups show no significant regulation. Based on siRNA experiments we could propose AP-1 and GATA-2 as potential co-activators for the PML/RARα-dependent regulation of the miR-181a/b-cluster. In functional studies in NB4 cells we observed after lentiviral knock down of miR-181a and miR-181b a significant reduction of colony size and number as well as proliferation rate. In contrast, transient overexpression of miR-181a and miR-181b led to an inhibition of ATRA-induced expression of the differentiation marker CD11b. In a microRNA target search we identified the novel ATRA regulated tumor suppressor RASSF1A as a putative target of miR-181a and miR-181b. In functional studies we showed that enforced expression of miR-181a and miR-181b reduces the protein level of RASSF1A by binding to the 3´UTR of RASSF1A mRNA. Accordingly, RASSF1A protein was enriched after knock down of miR-181b. The role of RASSF1A in ATRA induced differentiation was verified by knock down of RASSF1A protein by specific siRNA: Here we could show the reduction of ATRA induced CD11b expression. Overexpression of RASSF1A in NB4 cells strongly induced apoptosis. Additional, we could show by western blot that the miR-181a/b-cluster and RASSF1A modulate cell cycle via regulation of cyclin D1. In conclusion, we identified the miR-181a/b-cluster as an important player in the PML/RARα associated APL. Moreover, we firstly described the miR-181a/b target RASSF1A as a crucial factor in the ATRA activated granulocytic differentiation program in APL. Our data reveal the importance of deregulated microRNA biogenesis in cancer and may provide novel biomarkers and therapeutic targets in myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Retinoic acid is required for and potentiates differentiation of acute promyelocytic leukemia cells by nonretinoid agents

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2122-2129 ◽  
Author(s):  
A Chen ◽  
JD Licht ◽  
Y Wu ◽  
N Hellinger ◽  
W Scher ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Line ◽  
Acute Promyelocytic Leukemia ◽  
Drug Exposure ◽  
Primary Cultures ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Line ◽  
Granulocytic Differentiation ◽  
Nb4 Cells

Patients with acute promyelocytic leukemia (APL) associated with the t(15;17) translocation and fusion of the promyelocytic leukemia (PML) and retinoic acid receptor-alpha (RAR-alpha) genes achieve complete remission but not cure with all-trans retinoic acid (RA), NB4, a cell line derived from a patient with t(15;17) APL that undergoes granulocytic differentiation when treated with pharmacologic doses of RA, was used as a model for differentiation therapy of APL. We found that NB4 cells are resistant to differentiation by nonretinoid inducers such as hexamethylene bisacetamide (HMBA), butyrates, vitamin D3, or hypoxanthine, all of which can induce differentiation in the commonly used HL60 leukemia cell line. Preexposure of NB4 cells to low concentrations of RA for a period as short as 30 minutes abolished resistance to nonretinoids and potentiated differentiation. Sequential RA and HMBA treatment yielded maximal differentiation by 3 days of drug exposure, whereas the effect of RA alone peaked after 6 days and yielded a smaller percentage of differentiated cells. RA also reversed NB4 cell resistance to butyrates and allowed for synergistic differentiation by these agents. Pretreatment with HMBA before exposure to RA failed to stimulate differentiation. Sequential RA/HMBA treatment also markedly increased the extent of differentiation of primary cultures of bone marrow and peripheral blood mononuclear cells from three APL patients. In one case RA/HMBA treatment overcame resistance to RA in vitro. Together, these results suggest that intermittent low doses of RA followed by either HMBA or butyrates may be a useful combination in the treatment of APL. This clinical strategy may help prevent or overcome RA resistance in APL.

scholarly journals Targeting PML-RARαand Oncogenic Signaling Pathways by Chinese Herbal MixtureTien-HsienLiquid in Acute Promyelocytic Leukemia NB4 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Chih-Jung Yao ◽  
Chia-Ming Yang ◽  
Shuang-En Chuang ◽  
Jiann-Long Yan ◽  
Chun-Yen Liu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Acute Promyelocytic Leukemia ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Gel Chromatography ◽  
Oncogenic Signaling ◽  
Nb4 Cells ◽  
Chinese Herbal ◽  
Oncogenic Signaling Pathways

Tien-HsienLiquid (THL) is a Chinese herbal mixture that has been used worldwide as complementary treatment for cancer patients in the past decade. Recently, THL has been shown to induce apoptosis in various types of solid tumor cellsin vitro. However, the underlying molecular mechanisms have not yet been well elucidated. In this study, we explored the effects of THL on acute promyelocytic leukemia (APL) NB4 cells, which could be effectively treated by some traditional Chinese remedies containing arsenic trioxide. The results showed THL could induce G2/M arrest and apoptosis in NB4 cells. Accordingly, the decrease of cyclin A and B1 were observed in THL-treated cells. The THL-induced apoptosis was accompanied with caspase-3 activation and decrease of PML-RARαfusion protein. Moreover, DNA methyltransferase 1 and oncogenic signaling pathways such as Akt/mTOR, Stat3 and ERK were also down-regulated by THL. By using ethyl acetate extraction and silica gel chromatography, an active fraction of THL named as EAS5 was isolated. At about 0.5–1% of the dose of THL, EAS5 appeared to have most of THL-induced multiple molecular targeting effects in NB4 cells. Based on the findings of these multi-targeting effects, THL might be regarding as a complementary and alternative therapeutic agent for refractory APL.

scholarly journals Regulation of Immune Cell Functions by Metabolic Reprogramming

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jaehong Kim
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Functional Plasticity ◽  
Inflammatory Reactions ◽  
Cell Functions

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

scholarly journals Effects of Fifty-Hertz Electromagnetic Fields on Granulocytic Differentiation of ATRA-Treated Acute Promyelocytic Leukemia NB4 Cells

2018 ◽  
Vol 46 (1) ◽  
pp. 389-400 ◽  
Author(s):  
Alfredo Errico Provenzano ◽  
Stefano Amatori ◽  
Maria Gemma Nasoni ◽  
Giuseppe Persico ◽  
Sergio Russo ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Electromagnetic Fields ◽  
Cellular Proliferation ◽  
Biological Effects ◽  
Promyelocytic Leukemia ◽  
Ros Generation ◽  
Granulocytic Differentiation ◽  
Nb4 Cells ◽  
Oxidative Balance

Background/Aims: Life on Earth is constantly exposed to electromagnetic fields (EMFs) and the effects induced by EMFs on biological systems have been extensively studied producing different and sometimes contradictory results. Extremely low-frequency electromagnetic fields (ELF-EMFs) have shown to play a role in regulating cell proliferation and differentiation, although how EMFs influence these processes remains unclear. Human acute promyelocytic leukemia (APL) cells are characterized by the arrest of differentiation at the promyelocytic stage due to epigenetic perturbations induced by PML/RARα fusion protein (Promyelocytic Leukemia protein - PML/Retinoic Acid Receptor alpha - RARα). Therapeutic administration of all-trans retinoic acid (ATRA) re-establishes the leukemogenic mechanism re-inducing the normal differentiation processes. Methods: We studied the effects of ELF-EMFs (50 Hz, 2 mT) on the ATRA-mediated granulocytic differentiation process of APL NB4 cells (a cell line established from the bone marrow of a patient affected by the acute promyelocytic leukemia) by monitoring cellular proliferation and morphology, nitrob lue tetrazolium (NBT) reduction and the expression of differentiation surface markers. Finally, we investigated mechanisms focusing on reactive oxygen species (ROS) generation and related molecular pathways. Results: ELF-EMF exposure decreases cellular proliferation potential and helps ATRA-treated NB4 cells to mature. Furthermore, the analysis of ROS production and the consequent extracellular signal regulated kinases (ERK1/2) phosphorylation suggest that a changed intracellular oxidative balance may influence the biological effects of ELF-EMFs. Conclusions: These results indicate that the exposure to ELF-EMF promotes ATRA-induced granulocytic differentiation of APL cells.

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