scholarly journals 9-(2-Phosphonyl-methoxyethyl)-adenine promotes erythrocytic differentiation and disrupts cell replication in chronic myelogenous leukemia K562 cells

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Brittany Wiseman
Keyword(s):  
Cancer Treatment ◽  
Cancer Cells ◽  
Chronic Myelogenous Leukemia ◽  
Cellular Differentiation ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Cell Replication ◽  
Protein Subunit ◽  
Hematopoietic Stem ◽  
Gamma Globin

Disruption during cellular differentiation can cause hematopoietic stem cells to proliferate uncontrollably, resulting in the development of cancer. Differentiation therapies are being investigated as a type of cancer treatment which involve inducing agents that promote the differentiation of cancer cells into those with similar properties to normal blood cells. These cells can then undergo apoptosis at an accelerated and controlled rate compared to cancer cells, making this a potential therapeutic technique. In this study, the ability of human chronic myelogenous leukemia K562 cells to undergo cellular differentiation in response to the inducing agent 9-(2-Phosphonyl-methoxy ethyl)-adenine (PMEA) is investigated. PMEA has previously been shown to disrupt cell replication, and promote erythrocytic differentiation in K562 cells. In order to further test the effectiveness of this inducer, cell proliferation was measured with a cell growth curve, hemoglobin presence was measured with benzidine staining, and gamma-globin expression (a protein subunit of fetal hemoglobin) was measured in both induced and uninduced K562 cell cultures via RT-qPCR and western blotting. The results indicate that PMEA slows cell replication, and promotes hemoglobin (and subsequently gamma-globin) expression in treated cells. In summary, the findings support the conclusion that PMEA is able to promote erythrocytic differentiation in K562 cells, and provides information that supports differentiation therapies as a method for cancer treatment.

scholarly journals Activation-dependent alpha5beta1 integrin-mediated adhesion to fibronectin decreases proliferation of chronic myelogenous leukemia progenitors and K562 cells

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2450-2458 ◽  
Author(s):  
BI Lundell ◽  
JB McCarthy ◽  
NL Kovach ◽  
CM Verfaillie
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Hla Dr ◽  
Affinity Modulation ◽  
Marrow Stroma ◽  
Beta1 Integrin ◽  
Energy Dependent

Chronic myelogenous leukemia (CML) is a malignant disease of the hematopoietic stem cell characterized by abnormal circulation and proliferation of malignant progenitors. In contrast to their normal counterparts, CML progenitors adhere poorly to bone marrow stroma or fibronectin (FN). Aside from anchoring progenitors in the marrow microenvironment, beta1 integrin-dependent adhesion of normal progenitors is also associated with inhibition of their proliferation. As the beta1 integrin expression on CML progenitors is normal, we hypothesized that decreased integrin affinity may underlie the abnormal adhesive and proliferative characteristics of CML progenitors. We examined the effect of affinity modulation by the activating antibody 8A2 on the adhesion and proliferation of CML progenitors and the CML cell line, K562. 8A2 induced alpha5Beta1-dependent adhesion of Philadelphia chromosome-positive (Ph+) CD34+/HLA-DR+ cells and K562 cells to FN. Increased adhesion was 8A2- and FN concentration- dependent, time-dependent, and energy-dependent. Further, 8A2-induced adhesion to FN significantly inhibited the proliferation of malignant CML progenitors as well as K562 cells independent of cell differentiation, necrosis, or apoptosis. These studies demonstrate that affinity modulation of the alpha5Beta1 integrin on CML progenitors and K562 cells by 8A2 results in increased adhesion to FN with subsequent decreased proliferation, suggesting that decreased beta1 integrin affinity contributes to the abnormal circulation and proliferation of malignant progenitors in CML.

scholarly journals Personalized Immunotherapy Treatment Strategies for a Dynamical System of Chronic Myelogenous Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2030
Author(s):  
Paul A. Valle ◽  
Luis N. Coria ◽  
Corina Plata
Keyword(s):  
Dynamical System ◽  
Cancer Cells ◽  
Chronic Myelogenous Leukemia ◽  
Sufficient Conditions ◽  
Treatment Strategies ◽  
Myelogenous Leukemia ◽  
Invariant Sets ◽  
Cellular Immunotherapy ◽  
Complete Eradication ◽  
Treatment Parameter

This paper is devoted to exploring personalized applications of cellular immunotherapy as a control strategy for the treatment of chronic myelogenous leukemia described by a dynamical system of three first-order ordinary differential equations. The latter was achieved by applying both the Localization of Compact Invariant Sets and Lyapunov’s stability theory. Combination of these two approaches allows us to establish sufficient conditions on the immunotherapy treatment parameter to ensure the complete eradication of the leukemia cancer cells. These conditions are given in terms of the system parameters and by performing several in silico experimentations, we formulated a protocol for the therapy application that completely eradicates the leukemia cancer cells population for different initial tumour concentrations. The formulated protocol does not dangerously increase the effector T cells population. Further, complete eradication is considered when solutions go below a finite critical value below which cancer cells cannot longer persist; i.e., one cancer cell. Numerical simulations are consistent with our analytical results.

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

2003 ◽  
Vol 94 (6) ◽  
pp. 557-563 ◽  
Author(s):  
Motoi Mukai ◽  
Xiao-Fang Che ◽  
Tatsuhiko Furukawa ◽  
Tomoyuki Sumizawa ◽  
Shunji Aoki ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Human Chronic Myelogenous Leukemia

scholarly journals Clonal analysis of bcr-abl rearrangement in T lymphocytes from patients with chronic myelogenous leukemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
D Jonas ◽  
M Lubbert ◽  
ES Kawasaki ◽  
M Henke ◽  
KJ Bross ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Precursor Cell ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
T Cell Clones ◽  
Cell Clones

The cytogenetic hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph1), which reflects a chromosomal translocation t(9;22) and a rearrangement of the ABL and bcr genes. This marker is found in all cells arising from the same malignant precursor cell and can be detected in CML cells of the myeloid, monocytic, erythroid, and B-lymphocyte lineage. It is, however, controversial as to whether T lymphocytes of CML patients carry this gene rearrangement. An answer to this question would clarify whether the translocation in CML occurs in a pluripotent hematopoietic stem cell or in a precursor cell already committed to certain lineages, but not the T-cell lineage. To address this question, we established T-cell clones from peripheral venous blood cells of four patients with CML and screened these clones for bcr-abl fusion transcripts by means of polymerase chain reaction and Southern blot analysis. In four T-cell clones of three of these patients, the bcr-abl transcript could be detected. None of 12 T-cell clones of the fourth patient disclosed detectable bcr-abl amplification product. Both CD4+ as well as CD8+ clones displayed fused bcr-abl sequences. These data imply that in CML some but not all T lymphocytes may originate from the Ph1-positive stem cell.

scholarly journals Polyclonal hematopoiesis in interferon-induced cytogenetic remissions of chronic myelogenous leukemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 997-1002 ◽  
Author(s):  
D Claxton ◽  
A Deisseroth ◽  
M Talpaz ◽  
C Reading ◽  
H Kantarjian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Gene Polymorphism ◽  
Chronic Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Clonality Analysis ◽  
Ifn Therapy ◽  
Cytogenetic Remission ◽  
The One

Interferon (IFN) therapy of early chronic myelogenous leukemia (CML) frequently produces partial or complete cytogenetic remission of the disease. Patients with complete cytogenetic remission often continue on therapy for several years with bone marrow showing only diploid (normal) metaphases. We studied hematopoiesis in five female patients with major cytogenetic remissions from CML during IFN therapy. Clonality analysis using the BstXI PGK gene polymorphism showed that granulocytes were nonclonal in all patients during cytogenetic remission. BCR region studies showed rearrangement only in the one patient whose remission was incomplete at the time of sampling. Granulopoiesis is nonclonal in IFN-induced remissions of CML and may be derived from normal hematopoietic stem cells.

scholarly journals BCR-ABL Activity Is Critical for the Immunogenicity of Chronic Myelogenous Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2202-2202
Author(s):  
Katharina M. Brauer ◽  
Daniela Werth ◽  
Karin von Schwarzenberg ◽  
Anita Bringmann ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Antigen Presenting Cells ◽  
K562 Cells ◽  
Cytolytic Activity ◽  
Myelogenous Leukemia ◽  
51Cr Release ◽  
Antigen Presenting ◽  
Ctl Responses

Abstract Imatinib mesylate (Gleevec®) is a specific tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. In the treatment of chronic myelogenous leukemia (CML) it has become indispensable and shows few side effects. Recently, it was shown that patients treated with imatinib showed impaired CTL responses in comparison to patients treated with IFN-α, which might be due to a reduced immunogenicity of CML cells or result from an inhibitory effect of imatinib on the function of antigen presenting cells and T lymphocytes. In the present study, we show that imatinib treatment leads to a downregulation of immunogenic antigens on the CML cells, which in turn inhibits the development of CML-specific cytotoxic T lymphocytes (CTLs). To achieve this, we treated the CML cell line K562 and an imatinib-resistant K562 variant, K562R, with imatinib or DMSO, isolated the total RNA and used it to electroporate monocyte-derived dendritic cells (DCs). These cells were then used as antigen presenting cells (APCs) for the induction of polyclonal CTL responses. The cytolytic activity of the CTLs was assayed in standard 51Cr-release assays and their fine specificity in IFNγ-Elispot assays. CTLs generated using RNA from imatinib-treated K562 cells were completely incapable of specific killing and did not react in Elispot assays, whereas those CTLs induced using RNA from K562 cells subjected to DMSO treatment as well as RNA from imatinib-treated K562R cells showed specific cytolytic activity against targets electroporated with RNA from CML cells and were able to recognize several CML-associated antigens, like survivin, PRAME, WT-1 and PR3 in Elispot assays. To confirm that this effect is mediated by BCR-ABL inhibition, we used specific siRNA against the bcr-abl fusion site b3a2 to downregulate the protein expression and found essentially the same results. Even in K562R cells, that constitutively overexpress BCR-ABL, targeting the expression of the protein directly by specific siRNA leads to an impairment of CTL induction. In order to confirm and expand these studies, we additionally analyzed the expression of antigens connected to immune responses to CML in Western Blot and Real-time PCR experiments. We found, that imatinib-mediated inhibition of BCR-ABL in K562 cells leads to a decreased expression of tumor antigens and cellular proteins including survivin, adipophilin, hTERT, WT-1, Bcl-xL and Bcl-2 in correlation to the decreased development of specific CTLs. Matching the results of the 51Cr-release assays, these effects were not observed in K562R cells. In primary CML cells subjected to imatinib a downregulation of hTERT and survivin could be detected, which corresponded to a decreased lysis of DCs electroporated with RNA from these cells in standard 51Cr-release assays. Our results demonstrate, that BCR-ABL directly influences the expression of immunogenic tumor associated antigens by its uncontrolled tyrosine kinase activity and therefore substantially contributes to the immunogenicity of CML cells.

scholarly journals A Novel Methoxybenzyl 5-Nitroacridone Derivative Effectively Triggers G1 Cell Cycle Arrest in Chronic Myelogenous Leukemia K562 Cells by Inhibiting CDK4/6-Mediated Phosphorylation of Rb

2020 ◽  
Vol 21 (14) ◽  
pp. 5077
Author(s):  
Bin Zhang ◽  
Ting Zhang ◽  
Tian-Yi Zhang ◽  
Ning Wang ◽  
Shan He ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chronic Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
G1 Phase ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.

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