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

2019 ◽  
Vol 70 (9) ◽  
pp. 3193-3196 ◽  
Author(s):  
Emilia Georgiana Pascu ◽  
Mihnea Alexandru Gaman ◽  
Cornel Moisa ◽  
Amelia Maria Gaman
Keyword(s):  
Oxidative Stress ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Compensatory Mechanism ◽  
Stress Levels ◽  
Tki Treatment

Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome. Oxidative stress is involved in CML etiopathogenesis and disease progression, as well as the response to tyrosine kinase inhibitors (TKI) treatment. We evaluated oxidative stress levels in 47 CML patients vs. controls. The total antioxidant capacity (TAC) was measured using a FLUOstar Omega microplate reader (reagents from Sigma-Aldrich). Cellular reactive oxygen species (ROS) were evaluated using a CyFlow SPACE Sysmex flow-cytometer (reagents from Abcam). Oxidative stress levels were higher in CML patients vs. controls. The maximum TAC value and the minimum ROS value were recorded in CML patients with a BCR-ABL1 transcript value of 0.1-1%, suggesting that the production of plasma antioxidants progressively increases as a compensatory mechanism in CML patients undergoing TKI treatment in order to annihilate ROS. The pseudonormalization of the cell redox status observed in these patients could be an alarm signal prior to the development of resistance to TKI treatment or disease progression.

Effect of Dasatinib on Genes Related to Mitotic Catastrophe Pathway in Chronic Myeloid Leukemia Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Sezgi Kipcak ◽  
Buket Ozel ◽  
Cigir B. Avci ◽  
Leila S. Takanlou ◽  
Maryam S. Takanlou ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Mitotic Catastrophe ◽  
Control Group ◽  
Cancer Therapies ◽  
Apoptosis Pathways

Background: Chronic myeloid leukemia (CML), is characterized by a reciprocal translocation t(9;22) and forms the BCR/ABL1 fusion gene, which is called the Philadelphia chromosome. The therapeutic targets for CML patients which are mediated with BCR/ABL1 oncogenic are tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib. The latter two of which have been approved for the treatment of imatinib-resistant or intolerance CML patients. Mitotic catastrophe (MC) is one of the non-apoptotic mechanisms which frequently initiated in types of cancer cells in response to anti-cancer therapies; pharmacological inhibitors of G2 checkpoint members or genetic suppression of PLK1, PLK2, ATR, ATM, CHK1, and CHK2 can trigger DNA-damage-stimulated mitotic catastrophe. PLK1, AURKA/B anomalously expressed in CML cells, that phosphorylation and activation of PLK1 occur by AURKB at centromeres and kinetochores. Objective: The purpose of this study was to investigate the effect of dasatinib on the expression of genes in MC and apoptosis pathways in K562 cells. Methods: Total RNA was isolated from K-562 cells treated with the IC50 value of dasatinib and untreated cells as a control group. The expression of MC and apoptosis-related genes were analyzed by the qRT-PCR system. Results: The array-data demonstrated that dasatinib-treated K562 cells significantly caused the decrease of several genes (AURKA, AURKB, PLK, CHEK1, MYC, XPC, BCL2, and XRCC2). Conclusion: The evidence supply a basis to support clinical researches for the suppression of oncogenes such as PLKs with AURKs in the treatment of types of cancer especially chronic myeloid leukemia.

scholarly journals Chronic Myeloid Leukemia and Cesarean Section: The Anesthesiologist’s Point of View

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Houssam Rebahi ◽  
Mourad Ait Sliman ◽  
Ahmed-Rhassane El Adib
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cesarean Section ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematologic Malignancy ◽  
Blast Crisis ◽  
Myeloproliferative Neoplasm ◽  
Point Of View ◽  
Poor Outcomes ◽  
Challenging Situation

Background. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm related to chromosomal reciprocal translocation t(9;22). Tyrosine kinase inhibitors (TKIs) such as imatinib have drastically revolutionized the course and the prognosis of this hematologic malignancy. As we know, the association pregnancy-CML is an infrequent situation. Also the use of TKI in pregnant women is unsafe with a lack of alternatives and effective therapeutic options. Thus its cessation during gestation puts those patients at high risk of developing blast crisis characterized by poor outcomes.Case Report. A 37-year-old pregnant woman, gravida 2, para 2, with a previous cesarean section in 2011, presented to the obstetric unit. Her medical past revealed that she is a newly diagnosed patient with CML managed by TKI during her preconception period. Due to the perilous use of TKI during her pregnancy, a switch to interferon-αadministration was adopted. But after the completion of 36 weeks of gestation, disease progression (relapse with blast crisis), attested by biological worsening, a white blood cell count = 245000/mm3with 32% blasts in the peripheral blood, urged the medical team to opt for cesarean delivery. She underwent general endotracheal anesthesia without any perioperative incidents and gave birth to a healthy newborn. Ten days later, the patient was started on TKI.Discussion. Although data on this specific and challenging situation are limited, this case highlights the difficulties encountered by the anesthesiologists when choosing the accurate anesthetic strategy and how important it is to weigh the risks and benefits inherent to each technique. Above all, taking into consideration the possible central nervous system (CNS) contamination by circulating blast cells when performing spinal or epidural approach is primordial. This potential adverse event (CNS blast crisis) is extremely scarce but it is responsible for high rates of morbidity and mortality.

scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

scholarly journals Organic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myeloid Leukemia

2019 ◽  
Vol 18 ◽  
pp. 153303381987990 ◽  
Author(s):  
Mohammed Hussein Kamareddine ◽  
Youssef Ghosn ◽  
Antonios Tawk ◽  
Carlos Elia ◽  
Walid Alam ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chronic Myeloid Leukemia ◽  
Fusion Protein ◽  
Myeloid Leukemia ◽  
Drug Delivery Systems ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Delivery Systems ◽  
Treatment Modalities ◽  
Organic Nanoparticles

Chronic myeloid leukemia is a myeloproliferative neoplasm that occurs more prominently in the older population, with a peak incidence at ages 45 to 85 years and a median age at diagnosis of 65 years. This disease comprises roughly 15% of all leukemias in adults. It is a clonal stem cell disorder of myeloid cells characterized by the presence of t(9;22) chromosomal translocation, also known as the Philadelphia chromosome, or its byproducts BCR-ABL fusion protein/messenger RNA, leading to the expression of a protein with enhanced tyrosine kinase activity. This fusion protein has become the main therapeutic target in chronic myeloid leukemia therapy, with imatinib displaying superior antileukemic effects, placing it at the forefront of current treatment protocols and displaying great efficacy. Alternatively, nanomedicine and employing nanoparticles as drug delivery systems may represent new approaches in future anticancer therapy. This review focuses primarily on the use of organic nanoparticles aimed at chronic myeloid leukemia therapy in both in vitro and in vivo settings, by going through a thorough survey of published literature. After a brief introduction on the pathogenesis of chronic myeloid leukemia, a description of conventional, first- and second-line, treatment modalities of chronic myeloid leukemia is presented. Finally, some of the general applications of nanostrategies in medicine are presented, with a detailed focus on organic nanocarriers and their constituents used in chronic myeloid leukemia treatment from the literature.

Patients with Chronic Myeloid Leukemia with Variant Philadelphia Chromosome (Ph) Translocations Have a Similar Outcome as Those with Classic Ph When Treated with Imatinib or 2nd Generation TKI

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3228-3228 ◽  
Author(s):  
Nicolas Batty ◽  
Hagop Kantarjian ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Initial Therapy ◽  
P Value ◽  
Limited Information ◽  
2Nd Generation ◽  
Chromosome Variant

Abstract Background: Variant Philadelphia chromosome (Ph) translocations frequently involving 1-2 additional chromosomes besides 9 and 22 and represent 5–10% of patients (pts) with chronic myeloid leukemia (CML). The European LeukemiaNet recommendations provide a warning for patients with variant translocations, although there is limited information about their outcome after therapy with tyrosine kinase inhibitors (TKI). Our prior analysis mostly among pts who had failed prior interferon suggested that these pts had similar outcome to those with classic Ph translocations when treated with imatinib (El-Zimaity et al; Br. J Haematol 2004). Aims: To explore the characteristics and outcome of patients with variant translocations treated with frontline imatinib or 2nd generation TKI (dasatinib or nilotinib) after imatinib failure. Methods: We reviewed the outcome of all pts with CML treated at our institution in 3 groups: early chronic phase (CP) receiving imatinib as initial therapy, and CP treated with 2nd generation TKI after Imatinib failure, accelerated phase (AP) treated with 2nd TKI after imatinib failure. Results of pts with variant Ph were compared to those with classic Ph. Results: Among 554 pts (278 CP frontline imatinib, 190 CP post imatinib failure, 86 AP post Imatinib failure) 33 (6%) had variant Ph (21[8%], 6[3%], 6[7%], in each of the 3 groups, respectively). Median follow up is 55 months (mo) (2 – 90), 24 (1 – 53) mo and 29 (5 – 46) mo, respectively, for the 3 groups. Results are summarized in the following tables: Frontline Imatinib Therapy Percentage Variant Ph Classic Ph P value N=21 N=255 MCyR 95 95 1 CCyR 86 89 0.49 2-yr EFS 83 93 0.93 2-yr TFS 94 96 0.7 2-yr OS 100 99 0.48 Second generation TKI Variant Ph Chromosome Variant Ph Classic Ph P value Chronic Phase N = 6 N = 78 MCyR 100 75 0.34 CCyR 100 72 0.34 2-yr EFS 100 80 0.27 2-yr OS 100 98 0.71 Accelerated Phase N=6 N=80 MCyR 33 38 1 CCyR 33 32 1 2-yr EFS 25 41 0.41 2-yr OS 100 89 0.44 Conclusion: Pts with variant Ph have a similar prognosis to those with classic Ph translocations when treated with imatinib as initial therapy or with 2nd generation TKI after imatinib failure. The warning category for these patients may no longer be needed in the era of TKI.

scholarly journals Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5697-5700 ◽  
Author(s):  
Franck Emmanuel Nicolini ◽  
Grzegorz W. Basak ◽  
Simona Soverini ◽  
Giovanni Martinelli ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Blast Phase

Abstract T315I+ Philadelphia chromosome–positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABLT315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome–positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABLT315I mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors.

scholarly journals Atypical Chronic Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5455-5455
Author(s):  
Chandralekha Ashangari ◽  
Praveen K. Tumula
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Peripheral Blood Flow ◽  
Current Standard ◽  
Atypical Chronic Myeloid Leukemia ◽  
Wbc Count

Abstract Introduction: Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. We present one of the rare presentations of aCML in an elderly patient. Case: A 76 year old male presented to the Hematology clinic for consultation after discharge from local hospital for elevated WBC count. Past medical history was significant for COPD, acid reflux, peripheral arterial disease and hypertension. Physical exam was unremarkable. Initial labs were significant for leukocytosis of 30 k/cu mm, anemia with Hb 10 gm/dl, thrombocytosis 695,000 with neutrophilia of ANC 25,200. Peripheral blood was negative for JAK2 V617F and BCR-ABL. Peripheral blood flow cytometry showed granulocytic left shift with 1.5% myeloblasts. Bone marrow biopsy suggestive of hypercellular marrow (100%) with myeloid predominance, atypical megakaryocytes, increased ring sideroblasts (49% of NRBC), increased blasts (5%) and dysgranulopoeisis over all suggestive of Myelodyplastic Syndrome/Chronic Myeloproliferative Disorder (MDS/MPD). Cytogenetics were positive for U2AF1 positive, CSF3R T6181, CSF3R Q776 pathognomonicof atypical CML and negative for BCR-ABL, FLT3. He was considered transplant ineligible. He was started on Azacitadine and is currently receiving 2nd cycle therapy. He is also receiving darbepoeitin periodically to avoid frequent transfusions. He is currently transfusion independent. Discussion: Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood myeloid precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival in aCML. aCML cases lack in Philadelphia chromosome. Overall 50-65% of patients show cytogenetic abnormalities. The most frequent is +8 (25%). Other changes such as -7 and del(12p) have also been recurrently observed. Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Protein Damage and Antioxidant Status Alterations Caused by Oxidative Injury in Chronic Myeloid Leukemia

2016 ◽  
Vol 27 (2) ◽  
pp. 55 ◽  
Author(s):  
Deepti Pande ◽  
Reena Negi ◽  
Ranjana S. Khanna ◽  
Hari D. Khanna
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Chronic Myeloid Leukemia ◽  
Glutathione Peroxidase ◽  
Myeloid Leukemia ◽  
Antioxidant Status ◽  
Philadelphia Chromosome ◽  
Thiobarbituric Acid ◽  
Protein Carbonyl ◽  
Cellular Damage

Objective: To evaluate the oxidative stress and antioxidant defense in patients with chronic myeloid leukemia.Background: Chronic myeloid leukemia is a myeloproliferative disorder associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Reactive oxygen species and other free radicals mediate phenotypic and genotypic changes leading from mutation to neoplasia in all cancers, including chronic myeloid leukemia. We evaluated patients with chronic myeloid leukemia by observing their oxidative status and antioxidant defense.Methods: Using serum from 40 clinically diagnosed cases of chronic myeloid leukemia as well as 40 healthy controls, we measured the concentration of thiobarbituric acid, levels of protein carbonylation, total antioxidant status, catalase, superoxide dismutase, glutathione peroxidase, vitamins A and E, and the trace elements zinc, magnesium, and selenium. Results: We found significantly increased levels of serum malonyldialdehyde and protein carbonyl in patients with chronic myeloid leukemia in comparison to healthy individuals, and significantly decreased levels of the antioxidants and micronutrients thiobarbituric acid, catalase, superoxide dismutase, glutathione peroxidase, vitamins A and E, zinc, magnesium, and selenium. These data suggest cellular damage occurring at the level of lipids and proteins.Conclusion: These findings indicate a link between low levels of antioxidants and cellular damage in patients with chronic myeloid leukemia, supporting the idea that oxidative stress may play a role in the pathogenesis of chronic myeloid leukemia.

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