The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis (original) (raw)
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Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome
Leukemia Research, 2014
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it has been suggested that additional mutations lead to progression of MDS to AML, the causative agent(s) for such mutations remains unclear. Oxidative stress is a potential cause, therefore, we evaluated levels of reactive oxygen species (ROS) in NUP98-HOXD13 (NHD13) transgenic mice, a murine model for MDS. Increased levels of ROS were detected in bone marrow nucleated cells (BMNC) that express CD71, a marker for cell proliferation, as well as immature, lineage negative bone marrow nucleated cells from NHD13 mice. In addition to the increase in ROS, increased DNA double strand breaks and activation of a G2/M phase cell cycle checkpoint were noted in NHD13 BMNC. Finally, using an in vivo assay for mutation frequency, we detected an increased mutation frequency in NHD13 BMNC. These results suggest that oxidative stress may contribute to disease progression of MDS to AML through ineffective repair of DNA damage and acquisition of oncogenic mutations.
Reactive oxygen species overload promotes apoptosis in JAK2V617F-positive cell lines
Revista Brasileira De Hematologia E Hemoterapia, 2016
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), are characterized by excessive myeloid proliferation, with predominant megakaryocytic, erythroid, and megakaryocytic/granulocytic expansion, respectively, and have a potential of transformation to acute myeloid leukemia. 1 From the molecular point of view, the Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway plays an important role in the pathogenesis of MPNs. A recurrent gain-of-function mutation, V617F in JAK2, has been reported in most PV cases and in more than half of ET and PMF cases. 2 In JAK2V617F-negative patients, other gain-of-function mutations in genes related to JAK2/STAT signaling activation, including JAK2 exon 12, 3 MPL 4 and Calreticulin mutations, 5,6 have been identified. The current therapies for MPN are limited and do not result in the elimination of the malignant clone. The only curative approach for these diseases is allogeneic stem cell transplantation. 7 Ruxolitinib is a selective JAK1/2 inhibitor approved by the Food and Drug Administration (FDA) of the United States for the treatment of intermediate and high-risk PMF and PV patients with inadequate response or intolerance to hydroxyurea. Results from phase III clinical trials demonstrated that ruxolitinib is well tolerated, reduces inflammatory
Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes
Blood Advances, 2019
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM...
Oxidative stress is increased in primary and post−polycythemia vera myelofibrosis
Experimental Hematology, 2010
Objective. To determine if increased cell turnover in chronic myeloproliferative disorders can lead to hyperhomocysteinemia as a result of folate and/or cobalamin depletion, and contribute to oxidative stress. Materials and Methods. The clinical role of oxidative stress was investigated by measuring reactive oxygen species (ROS), total antioxidant capacity (TAC), and total homocysteine (tHcy), folate, cobalamin, and holotranscobalamin (HoloTC) levels in 51 chronic myeloproliferative disorders patients (male-to-female ratio: 1.1; median age: 64 years; range, 40L84 years), including 42 with primary myelofibrosis and 9 with postLpolycythemia vera myelofibrosis. Results. Myelofibrotic patients had higher tHcy (p [ 0.0201) and an unbalanced oxidative status (higher ROS and lower TAC levels; p ! 0.0001) than controls. Presence of diabetes or another neoplasia was associated with higher ROS levels (p ! 0.05), splenomegaly, hepatomegaly, and peripheral blasts with lower HoloTC levels (p ! 0.005). The most severe forms of myelofibrosis (2L3) were associated with lower TAC (p [ 0.045) and HoloTC levels (p [ 0.017). Patients with Janus kinase-2 mutations had lower HoloTC levels (p [ 0.0059). HoloTC deficiency was more frequently associated with Janus kinase-2 homozygosity (p ! 0.0003). Conclusions. Our findings suggest that the determination of HoloTC, tHcy, ROS concentrations, and TAC, can identify latent cobalamin deficiency and provide a rational basis for correcting the increased oxidation associated with disease progression. Ó
Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells
International journal of molecular sciences, 2015
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.
Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia
Biomolecules, 2022
Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the proliferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H2O2 activity compared to healthy subjects. Mo...
Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis
Blood, 2014
myelofibrosis in primary MPL , or CALR , JAK2 Clinical effect of driver mutations of http://www.bloodjournal.org/content/124/7/1062.full.html Updated information and services can be found at: (1258 articles) Myeloid Neoplasia (3942 articles) Clinical Trials and Observations Articles on similar topics can be found in the following Blood collections http://www.bloodjournal.org/site/misc/rights.xhtml#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
PloS one, 2014
Gene expression profi ling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have unraveled signifi cant deregulation of several immune and infl ammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might be downregulation of major histocompatibility (MHC) class I and II genes, which are used by tumor cells to escape antitumor T-cell-mediated immune responses. We have performed whole blood transcriptional profi ling of genes encoding human leukocyte antigen (HLA) class I and II molecules, beta2microglobulin and members of the antigen processing machinery of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). The fi ndings of signifi cant downregulation of several of these genes may likely be of major importance for defective tumor immune surveillance. Since up-regulation of HLA-genes are recorded during treatment with epigenome modulating agents (DNA-hypometylators and DNA-hyperacetylators (histone deacetylase inhibitors)) and interferon-alpha2 our fi ndings call for prospective transcriptional studies of HLA-genes during treatment with these agents.
Molecular oncology, 2018
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro-inflammatory cytokines resulting in chronic inflammation and genomic instability. Beside the driver mutations in JAK2, MPL and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR-382-5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease of SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate tha...