Oxidases and reactive oxygen species during hematopoiesis: A focus on megakaryocytes

Eliades, Alexia; Matsuura, Shinobu; Ravid, Katya

doi:10.1002/jcp.24071

Cited by 29 publications

(20 citation statements)

References 134 publications

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“…ROS are well known to have diverse biological consequences, which are tissue specific. [54][55][56][57] ROS has also been implicated previously as a determinant of MSC behavior [58][59][60][61] in cancer patients. We document that a ROS inhibitor not only blocked BM MSC proliferation but also reduced the expression of genes associated with osteoblastic differentiation.…”

Section: Discussionmentioning

confidence: 90%

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Lü

Xia

Liu

et al. 2015

Blood

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Key Points• LCN2 acts to generate reactive oxygen species, leading to increased DNA strand breaks and apoptosis in normal CD34 1 cells.• LCN2 promotes the generation of osteoblasts but diminishes adipogenesis, resembling the composition of the MF marrow microenvironment.Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34 1 cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. (Blood. 2015;126(8):972-982)

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Section: Discussionmentioning

confidence: 90%

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Lü

Xia

Liu

et al. 2015

Blood

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“…Here we show that unstimulated AML blasts from 60% of patients constitutively produce large amounts of extracellular superoxide, primarily via NOX family oxidases. NOX-derived ROS are known to play several key roles in normal hematopoiesis including hematopoietic stem cell (HSC) motility, 36 growth factor signaling, 9,10 and differentiation. 37 Other studies demonstrate a key role for ROS in regulating HSC selfrenewal 32,38,39 ; however, the role of NOX oxidases in this process is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling

Hole

Zabkiewicz

Munje

et al. 2013

Blood

195

222

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Key Points• More than 60% of primary AML blasts constitutively produce high levels of NOXderived reactive oxygen species (ROS), which drives AML proliferation.• High ROS AMLs show depleted antioxidant defenses but evade the oxidative stress response through suppression of p38 MAPK signaling.Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts, and, to a lesser extent, normal CD34 1 cells, and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38 MAPK. Consistent with this, we observed that p38 MAPK responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also develop mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone. (Blood. 2013;122(19):3322-3330)

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“…Although there is also opposite evidence, i.e. the leukemic cells being able to influence bone cells (Eisenberg et al 2009;Eliades et al 2012), it seems likely that the defect in osteoblast maturation in SSAT mice is due to the intrinsic SSAT activity rather than extrinsic signals, as demonstrated by in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of spermidine/spermine N 1-acetyltransferase impairs osteoblastogenesis and alters mouse bone phenotype

et al. 2014

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Spermidine/spermine N (1)-acetyltransferase (SSAT) is a catabolic regulator of polyamines, ubiquitous molecules essential for cell proliferation and differentiation. In pathological conditions, the increased polyamine catabolism has been shown to mediate its cellular functions not only by changed polyamine levels but also by the availability of metabolites shared with other metabolic pathways or by production of toxic compounds. Our previous results showed that mice overexpressing SSAT (SSAT mice) developed a myeloproliferative disease and the bone marrow microenvironment partly contributed to its development. In this study, the physiological role of SSAT and polyamines in bone remodeling was characterized. Skeletal development of the SSAT mice appeared outwardly similar to wild-type mice until maturity, after which the SSAT mice developed kyphosis. With aging, the SSAT overexpression elicited increased bone perimeter with strikingly thinned cortical bone, decreased trabecular thickness and increased trabecular number in mice. In vitro studies showed that the maturation of SSAT overexpressing osteoblasts was impaired and the expression of bone formation marker genes was dramatically decreased. The polyamine pattern in osteoblasts of SSAT mice was distorted in comparison with wild-type mice. However, treatment of osteoblasts with a SSAT-inducing functional polyamine analogue suggested that defective osteoblastogenesis resulted rather from other consequences of enhanced SSAT activity than lowered levels of the higher polyamines. In comparison to SSAT overexpressing mice, SSAT deficiency led to opposite changes in osteoblastogenesis and differences in bone phenotype in mice. In conclusion, the level of SSAT enzyme activity affected osteoblastogenesis and hence influenced bone remodeling and the bone phenotype in mice. Furthermore, our results suggest the contribution of the catabolic part of the polyamine cycle, other than polyamine depletion, in pathophysiological processes of bone remodeling.

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Oxidases and reactive oxygen species during hematopoiesis: A focus on megakaryocytes

Cited by 29 publications

References 134 publications

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling

Overexpression of spermidine/spermine N 1-acetyltransferase impairs osteoblastogenesis and alters mouse bone phenotype

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