scholarly journals Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study

2021 ◽  
Vol 10 (7) ◽  
pp. 1349
Author(s):  
Kamila Czubak-Prowizor ◽  
Jacek Trelinski ◽  
Paulina Stelmach ◽  
Piotr Stelmach ◽  
Agnieszka Madon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Exploratory Study ◽  
Myeloid Leukemia ◽  
Thiobarbituric Acid ◽  
Red Blood Cell Transfusion ◽  
Packed Red Blood Cells ◽  
Chronic Oxidative Stress ◽  
Total Antioxidant ◽  
Acute Myeloid

Chronic oxidative stress (OS) can be an important factor of acute myeloid leukemia (AML) progression; however, there are no data on the extent/consequence of OS after transfusion of packed red blood cells (pRBCs) and platelet concentrates (PCs), which are commonly used in the treatment of leukemia-associated anemia and thrombocytopenia. We aimed to investigate the effects of pRBC/PC transfusion on the OS markers, i.e., thiol and carbonyl (CO) groups, 3-nitrotyrosine (3-NT), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGE), total antioxidant capacity (TAC), SOD, GST, and LDH, in the blood plasma of AML patients, before and 24 h post-transfusion. In this exploratory study, 52 patients were examined, of which 27 were transfused with pRBCs and 25 with PCs. Age-matched healthy subjects were also enrolled as controls. Our results showed the oxidation of thiols, increased 3-NT, AGE levels, and decreased TAC in AML groups versus controls. After pRBC transfusion, CO groups, AGE, and 3-NT significantly increased (by approximately 30, 23, and 35%; p < 0.05, p < 0.05, and p < 0.01, respectively) while thiols reduced (by 18%; p < 0.05). The PC transfusion resulted in the raise of TBARS and AGE (by 45%; p < 0.01 and 31%; p < 0.001), respectively). Other variables showed no significant post-transfusion changes. In conclusion, transfusion of both pRBCs and PCs was associated with an increased OS; however, transfusing the former may have more severe consequences, since it is associated with the irreversible oxidative/nitrative modifications of plasma proteins.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

scholarly journals Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2229-2236 ◽  
Author(s):  
MJ Robertson ◽  
RJ Soiffer ◽  
AS Freedman ◽  
SL Rabinowe ◽  
KC Anderson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Red Blood Cell Transfusion ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Acute Myeloid

Abstract The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte- macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA- compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.

scholarly journals CHARACTERISTICS CHANGES IN PRO-OXIDANT-ANTIOXIDANT STATUS IN PATIENTS WITH ACUTE LEUKEMIA DURING CHEMOTHERAPY

2020 ◽  
Vol 20 (1) ◽  
pp. 23-28
Author(s):  
H.S. Maslova ◽  
I.M. Skrypnyk ◽  
O.F. Hopko
Keyword(s):  
Lipid Peroxidation ◽  
Acute Myeloid Leukemia ◽  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Catalase Activity ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Thiobarbituric Acid ◽  
Thiobarbituric Acid Reactive Substances ◽  
Acute Myeloid

Changes in the processes of lipid peroxidation and antioxidant system activity are involved in the pathogenesis of carcinogenesis and can affect tumor resistance to chemotherapy. The aim of this study to investigate the nature of changes in pro-oxidant-antioxidant status in patients with acute leukemia during remission induction chemotherapy.  Materials and methods. The study involved 42 patients with newly diagnosed acute leukemia, 22 of them were diagnosed to have acute myeloid leukemia and 20 patients had acute lymphoblastic leukemia. The age range was 18-58 years, there were 19 women (45.2%) and 23 men (54.8%). The patients were divided into two groups: I (n=22) included patients with acute myeloid leukemia, who had chemotherapy modes "7+3" and "5+2" for variants M0-2 and "7+3+etoposide" or "5+2+etoposide" for M4-5 variants; II (n=20) group included patients with acute lymphoblastic leukemia, who received chemotherapy according to D. Hoelzer protocol. Hemogram parameters (red blood cells, hemoglobin, white blood cells, platelets) were evaluated at baseline and on the 28th day of chemotherapy. The concentration of thiobarbituric acid reactive substances and catalase activity in the blood serum were assessed as well. Examination of acute myeloid leukemia patients was performed before the chemotherapy, on the 4th and 28th days since chemotherapy started; acute lymphoblastic leukemia patients were examined before chemotherapy, on the 23rd and 28th days. The group of healthy individuals consisted of 20 persons, including 9 (45%) women and 11 (55%) men, aged 22-26 years. Results. The detailed clinical picture of acute leukemia was accompanied by typical changes in hemogram in the patients of both test groups, and namely, by the development of leukocytosis, anemia, thrombocytopenia. At the same time, the patients with acute myeloid leukemia and acute lymphoblastic leukemia demonstrated an increased concentration of thiobarbituric acid reactive substances in 1.8 and 1.89 times, respectively (p<0.05) that was accompanied by an increased serum catalase activity in 1.96 and 1.8 times, respectively (p<0.05) compared to healthy individuals. During "7+3" chemotherapy, acute myeloid leukemia patients were found to show thiobarbituric acid reactive substances increased in 1.9 times on the 4th day of treatment and decreased on the 28th day.The patients with acute lymphoblastic leukemia managed according to the D. Hoelzer protocol demonstrated an increased concentration of thiobarbituric acid reactive substances in the blood serum in 1.33 times on the 23rd day of treatment (p<0.05), maintaining this level up to the 28th day. The catalase activity in the patients of the comparison groups did not change. Conclusion. The debut of acute leukemia is accompanied by activation of lipid peroxidation and antioxidant system enzymes. Сhemotherapy promotes the shift of the prooxidant-antioxidant equilibrium towards the lipid peroxidation activation.

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