Oxidative Stress and BCR-ABL1 Transcript Levels in Chronic Myeloid Leukemia: an Intricate Relationship

Pascu, Emilia Georgiana; Găman, Mihnea Alexandru; Moisă, Cornel; Găman, Amelia Maria

doi:10.37358/rc.19.9.7514

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…122 It seems that in myeloproliferative malignancies, oxidative stress is of great importance as a mechanism of tumorigenesis. [123][124][125] This reflects an imbalance between overproduction of reactive oxygen species and the cellular antioxidant defense. High levels of oxidative stress trigger cellular signaling pathways responsible for chronic inflammation, involved in tumorigenesis.…”

Section: Nlr and Lmr In Myeloproliferative Neoplasmsmentioning

confidence: 99%

The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies – A Narrative Review

Stefaniuk¹,

Szymczyk²,

Podhorecka³

2020

CMAR

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Despite the presence of many hematological prognostic indexes, clinical course and overall survival are often highly variable even within the same patient subgroup. Recent studies suggest that simple, cost-effective, low-risk tests such as neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ratio (LMR) may be used to evaluate the prognosis. Their role has been well confirmed in diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL) and multiple myeloma (MM), but until now the prognostic significance of NLR and LMR in leukemias has not been widely reported. In this article, we analyze the literature data on prognostic value of NLR and LMR in haematological malignancies in the context of classic prognostic factors and clinical course.

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Section: Nlr and Lmr In Myeloproliferative Neoplasmsmentioning

confidence: 99%

The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies – A Narrative Review

Stefaniuk¹,

Szymczyk²,

Podhorecka³

2020

CMAR

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“…Additionally, some results indicated that cells with acquired resistance exhibited intrinsically elevated levels of ROS when compared to susceptible cells [ 38 ]. It was also observed that measured antioxidant response increases over time in patients undergoing TKI-based chemotherapy and may precede the development of resistance to used chemotherapeutics [ 39 ]. On the other hand, it has been recently demonstrated that CML cells resistant to IM through T315I mutation exhibit a lower level of ROS production when compared to CML cells susceptible to IM action.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

et al. 2021

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Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous oxidative stress leading to genomic instability and development of TKI resistance. Model CML cells susceptible or resistant to IM, as well as wild-type, non-cancer cells without the BCR-ABL1 protein were treated with IM, hydrogen peroxide (H2O2) as a model trigger of external oxidative stress, or with IM+H2O2. Accumulation of reactive oxygen species (ROS), DNA damage, activity of selected antioxidant enzymes and glutathione (GSH), and mitochondrial potential (MMP) were assessed. We observed increase in ROS accumulation in BCR-ABL1 positive cells and distinct levels of ROS accumulation in IM-susceptible cells when compared to IM-resistant ones, as well as increased DNA damage caused by IM action in sensitive cells. Depletion of GSH levels and a decreased activity of glutathione peroxidase (GPx) in the presence of IM was higher in the cells susceptible to IM. IM-resistant cells showed an increase of catalase activity and a depletion of MMP. BCR-ABL1 kinase alters ROS metabolism, and IM resistance is accompanied by the changes in activity of GPx, catalase, and alterations in MMP.

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“…Oxidative stress has emerged as a putative mechanism in the development of BCR-ABL1 (+) and (-) myeloproliferative neoplasms. [36][37][38][39][40] Oxidative stress levels are higher in CML patients compared with healthy controls. 40 Oxidative stress levels are positively correlated with JAK2V617F mutational status and thrombotic complications in patients with essential thrombocythemia.…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38][39][40] Oxidative stress levels are higher in CML patients compared with healthy controls. 40 Oxidative stress levels are positively correlated with JAK2V617F mutational status and thrombotic complications in patients with essential thrombocythemia. 38 The biological roles of Alox12 in oxidative stress and NADPH homeostasis are complex and are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function

Si¹,

Hu²,

Yong³

2020

CMAR

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Introduction: Chronic myeloid leukemia (CML) is a myeloid malignancy characterized by the oncogene BCR-ABL. CML responds well to therapy targeting BCR-ABL in the chronic phase but is resistant to treatment when it progresses to the blast phase (BP). This study attempted to address whether arachidonate 12-lipoxygenase (Alox12) confers to CML drug resistance. Materials and Methods: We analyzed the expression of Alox12 using Western blotting, ELISA, and RT-PCR methods. Loss of functional analysis was performed using cellular activity assays on CML and normal hematopoietic stem/progenitor cells (HSPCs). Results: Alox12 and 12-Hydroxyeicosatetraenoic acid (12-HETE) are overexpressed in BP-CML but not HSPCs, and that Alox12-12-HETE axis is regulated by BCR-ABL. The Alox12-12-HETE axis is required for CML. Specific Alox12 inhibitor inhibits colony formation, survival, and self-renewal capacity in BP-CML HSPCs, and to a significantly greater extent than in normal HSPCs. Of note, the Alox12 inhibitor significantly augments dasatinib's efficacy in BP-CML HSPCs. Mechanism studies show that Alox12 inhibition does not affect activities of essential signaling pathways involved in maintaining stem cell function, such as Wnt, p53, and bone morphogenetic protein (BMP). In contrast, we show that Alox12 inhibition disrupts nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis and induces oxidative stress and damage in CML HSPCs and committed cells. Conclusion: Alox12-12-HETE axis is a specific and critical regulator of BP-CML HSPCs functions. Pharmacological inhibition of Alox12 may be useful in BP-CML.

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Oxidative Stress and BCR-ABL1 Transcript Levels in Chronic Myeloid Leukemia: an Intricate Relationship

Cited by 5 publications

References 25 publications

<p>The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies – A Narrative Review</p>

<p>The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies – A Narrative Review</p>

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

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