Intracellular Reactive Oxygen Species Mark and Influence the Megakaryocyte-Erythrocyte Progenitor Fate of Common Myeloid Progenitors

Shinohara, Akihito; Imai, Yumiko; Nakagawa, Masahiro; Takahashi, Tsuyoshi; Ichikawa, Motoshi; Kurokawa, Mineo

doi:10.1002/stem.1588

Cited by 33 publications

(27 citation statements)

References 57 publications

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“…Recent studies have begun to shed light on the ROS involved in modulating biological cell functions, cell signaling, and homeostasis in tumor cells (29). AML-M5, which is associated with older age, is an aggressive form of a malignant disorder of the hematopoietic system that is characterized by highly proliferative blast cells (30) and high WBC counts and serum LDH levels (31).…”

Section: Discussionmentioning

confidence: 99%

Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress

Zhou

Pan

Wei

et al. 2017

Clinical Cancer Research

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Purpose High levels of ROS and ineffective antioxidant systems contribute to oxidative stress, which affects the function of hematopoietic cells in acute myeloid leukemia (AML); however, the mechanisms by which ROS lead to malignant transformation in relapsed AML-M5 are not completely understood. We hypothesized that alterations in intracellular ROS would trigger AML-M5 relapse by activating the intrinsic pathway. Experimental Design We studied ROS levels and conducted JAB1/COPS5 and TRX gene expression analyses with blood samples obtained from 60 matched AML-M5 patients at diagnosis and relapse and conducted mechanism studies of Jab1’s regulation of Trx in leukemia cell lines. Results Our data showed that increased production of ROS and a low capacity of antioxidant enzymes were characteristics of AML-M5, both at diagnosis and at relapse. Consistently, increased gene expression levels of thioredoxin (TRX) and c-Jun activation domain-binding protein-1 (JAB1/COPS5) were associated with low overall survival rates in patients with AML-M5. In addition, stimulating AML-M5 cells with low concentrations of hydrogen peroxide led to increased Jab1 and Trx expression. Consistently, transfection of ectopic Jab1 into leukemia cells increased Trx expression, whereas silencing of Jab1 in leukemia cells reduced Trx expression. Mechanistically, Jab1 interacted with Trx and stabilized Trx protein. Moreover, Jab1 transcriptionally regulated Trx. Furthermore, depletion of Jab1 inhibited leukemia cell growth both in vitro and in vivo. Conclusions We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of AML-M5. Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5.

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Section: Discussionmentioning

confidence: 99%

Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress

Zhou

Pan

Wei

et al. 2017

Clinical Cancer Research

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“…63 ROS levels have been shown to be particularly low in MEP, and low levels of ROS in the common myeloid progenitor correlate with gene expression signatures that favor the MEP fate. 142 It is possible that correction of the high ROS levels in these immunodeficient mice may allow for development of a more complete immune system and simultaneously promote the quiescence and self-renewal of the human HSC through multiple mechanisms.…”

Section: Il2rgmentioning

confidence: 99%

Xenograft models for normal and malignant stem cells

Goyama

Wunderlich

Mulloy

2015

Blood

112

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The model systems available for studying human hematopoiesis, malignant hematopoiesis, and hematopoietic stem cell (HSC) function in vivo have improved dramatically over the last decade, primarily due to improvements in xenograft mouse strains. Several recent reviews have focused on the historic development of immunodeficient mice over the last 2 decades, as well as their use in understanding human HSC and leukemia stem cell (LSC) biology and function in the context of a humanized mouse. However, in the intervening time since these reviews, a number of new mouse models, technical approaches, and scientific advances have been made. In this review, we update the reader on the newest and best models and approaches available for studying human malignant and normal HSCs in immunodeficient mice, including newly developed mice for use in chemotherapy testing and improved techniques for humanizing mice without laborious purification of HSC. We also review some relevant scientific findings from xenograft studies and highlight the continued limitations that confront researchers working with human HSC and LSC in vivo. (Blood. 2015;125(17):2630-2640 Immunodeficient mice for studying normal and malignant human hematopoiesisSince immunodeficient mice were first used in biomedical research, there has been a continual effort to improve their utility and expand their applicability to more areas of research. Over the last decade, with the advent of widespread transgenic approaches and the understanding by researchers of the potential for these models in moving our understanding of biology forward, a number of genetically engineered animals have become available. For a comprehensive overview of the history and use of xenografting, the reader is directed to a number of recent reviews.

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“…36 ROS is also known to play a critical role in lineage decision of myeloid progenitors and can promote differentiation into GMP. 37 Therefore, it is possible that the increased ROS in Casp2 −/− mice contributes to the observed age-related DNA damage and aneuploidy, as well as the enhanced myeloid skewing with age.…”

Section: Discussionmentioning

confidence: 99%

Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

et al. 2016

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The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2−/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.

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Intracellular Reactive Oxygen Species Mark and Influence the Megakaryocyte-Erythrocyte Progenitor Fate of Common Myeloid Progenitors

Cited by 33 publications

References 57 publications

Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress

Jab1/Csn5–Thioredoxin Signaling in Relapsed Acute Monocytic Leukemia under Oxidative Stress

Xenograft models for normal and malignant stem cells

Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

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