scholarly journals AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells

Leukemia ◽  
2014 ◽  
Vol 28 (12) ◽  
pp. 2416-2418 ◽  
Author(s):  
M Nieborowska-Skorska ◽  
S Flis ◽  
T Skorski
Keyword(s):  
Reactive Oxygen Species ◽  
Chronic Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Imatinib Resistant

scholarly journals Reactive oxygen species in BCR-ABL1-expressing cells – relevance to chronic myeloid leukemia

2016 ◽  
Vol 64 (1) ◽  
Author(s):  
Joanna Antoszewska-Smith ◽  
Elzbieta Pawlowska ◽  
Janusz Błasiak
Keyword(s):  
Reactive Oxygen Species ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Continuous Production ◽  
Chromosomal Translocation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Tki Resistance ◽  
Stem And Progenitor Cells

Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells.  CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI-resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be involved in CML progression and TKI-resistance and warrant further study.

Modulation of reactive oxygen species by antioxidants in chronic myeloid leukemia cells enhances imatinib sensitivity through survivin downregulation

2008 ◽  
Vol 19 (10) ◽  
pp. 975-981 ◽  
Author(s):  
Jolie Kiemlian Kwee ◽  
Diogo Gomes Luque ◽  
Ana Carolina dos Santos Ferreira ◽  
Flavia da Cunha Vasconcelos ◽  
Karina Lani Silva ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Reactive Oxygen ◽  
Leukemia Cells ◽  
Oxygen Species

scholarly journals Parthenolide and DMAPT Induce Cell Death in Chronic Myeloid Leukemia Cells Via Generation of Reactive Oxygen Species

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4242-4242
Author(s):  
Gabriela Flores-López ◽  
Hector Mayani ◽  
María Antonieta Chávez-Gonzalez
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Reactive Oxygen ◽  
Hl60 Cell ◽  
Oxygen Species ◽  
Induce Cell Death

Abstract Chronic Myeloid Leukemia (CML) is a malignant hematologic disease characterized by the presence of a chromosomal alteration known as the Philadelphia Chromosome (Ph). Ph originates in Leukemia Stem Cells (LSC) and is caused by the reciprocal translocation between chromosome 9 and 22, giving rise to the Bcr-Abl oncogene, which produces a constitutively active tyrosine kinase -the BCR-ABL oncoprotein. This CML feature has made it possible the development of Tyrosine Kinase Inhibitors (TKI's) Imatinib, Dasatinib, and Nilotinib, which are able to inhibit BCR-ABL and take patients into molecular remission. However TKI's are not able to eliminate the population of LSC, which cause patients to relapse if treatment is discontinued. This has made it necessary search for alternative ways to eliminate LSC in CML patients. Parthenolide (PTL), a sesquiterpene lactone extracted from the feverfew plant (Thanacethum partenium), which has been used in folk medicine to treat inflammatory symptoms, has shown activity against LSC in Acute Myeloid Leukemia (AML). Recently Guzman and collaborators have developed an analog of PTL, named DMAPT, which is orally bioavailable. Both molecules have shown to be active inhibitors of NFkB and induce high levels of Reactive Oxygen Species (ROS) in LSC of AML. In the present study we asked whether CML cells (LSC, Progenitors and CML cell lines) are sensitive to PTL and DMAPT. Cell lines K562, Kcl-22 and HL60 (as an AML control) were cultured in liquid suspension cultures with increasing concentrations of PTL or DMAPT at a cell density of 300,000 cells per ml. At 24 hours of exposure, PTL and DMAPT showed significant induction of apoptosis at 7.5 µM and 10 µM, respectively. To determine whether NFkB activity is inhibited by PTL and DMAPT, K562, Kcl-22, HL60 cell lines, as well as CD34+ cells from a CML patient in Chronic phase where exposed to 7.5 µM PTL or 10 µM DMAPT. After 6 hours, protein lysis was induced and Western blots were performed with protein extracts from 250,000 cells per lane. Membranes where probed for Phosphorilated-p65, total p65 and b-actin as a loading control. We observed a decrease in the levels of phosphorylated p65 in cells treated with PTL and DMAPT, compared with untreated cells, while levels of total p65 remained constant. We had previosly used DCFDA stain and HMOX expression, to observe ROS induction in CML cells exposed to PTL. To asses if ROS induction is necessary for CML cell death we pretreated cells with N-acetyl cysteine (NAC), precursor of glutathione, for 1 hour before treating cells with 7.5 µM PTL or 10 µM DMAPT, and evaluated ROS levels by staining with Cell rox deep red, Mitosox-PE, and also assessing cell viability with YoPro-1 and 7AAD stain. After 6 hours of PTL treatment, we found that NAC pretreatment diminished ROS levels in cytoplasm and mitochondrial dysfunction when cells were treated with PTL. Pretreatment with NAC was able to rescue the majority of cells from apoptosis induced by PTL. Similar results were observed in cultures treated with DMAPT. Taken together, our results indicate that PTL and DMAPT were able to induce cell death via apoptosis in CML cells. This process seems to involve inhibition of p65 phosphorylation and an increase in ROS levels, which we found to be necessary for cell death to occur. Disclosures No relevant conflicts of interest to declare.

scholarly journals Microwaves from mobile phone induce reactive oxygen species but not DNA damage, preleukemic fusion genes and apoptosis in hematopoietic stem/progenitor cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matus Durdik ◽  
Pavol Kosik ◽  
Eva Markova ◽  
Alexandra Somsedikova ◽  
Beata Gajdosechova ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Mobile Phone ◽  
Progenitor Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Fusion Genes ◽  
Microscopy Imaging ◽  
Hematopoietic Stem

Abstract Exposure to electromagnetic fields (EMF) has been associated with the increased risk of childhood leukemia, which arises from mutations induced within hematopoietic stem cells often through preleukemic fusion genes (PFG). In this study we investigated whether exposure to microwaves (MW) emitted by mobile phones could induce various biochemical markers of cellular damage including reactive oxygen species (ROS), DNA single and double strand breaks, PFG, and apoptosis in umbilical cord blood (UCB) cells including CD34+ hematopoietic stem/progenitor cells. UCB cells were exposed to MW pulsed signals from GSM900/UMTS test-mobile phone and ROS, apoptosis, DNA damage, and PFG were analyzed using flow cytometry, automated fluorescent microscopy, imaging flow cytometry, comet assay, and RT-qPCR. In general, no persisting difference in DNA damage, PFG and apoptosis between exposed and sham-exposed samples was detected. However, we found increased ROS level after 1 h of UMTS exposure that was not evident 3 h post-exposure. We also found that the level of ROS rise with the higher degree of cellular differentiation. Our data show that UCB cells exposed to pulsed MW developed transient increase in ROS that did not result in sustained DNA damage and apoptosis.

Sign in / Sign up

Export Citation Format

Share Document