MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Ueda, Koki; Kumari, Rajni; Schwenger, Emily; Wheat, Justin C.; Bohorquez, Oliver; Narayanagari, Swathi Rao; Taylor, Samuel J.; Carvajal, Luis A.; Pradhan, Kith; Bartholdy, Boris; Todorova, Tihomira I.; Goto, Hiroki; Sun, Daqian; Shan, Jidong; Song, Yinghui; Montagna, Cristina; Xiong, Shunbin; Lozano, Guillermina; Pellagatti, Andrea; Boultwood, Jacqueline; Verma, Amit; Steidl, Ulrich

doi:10.1016/j.ccell.2021.02.006

Cited by 20 publications

(23 citation statements)

References 84 publications

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“…Conversion of MDS to AML is associated with MDMX overexpression, a p53 regulator 96 . MDMX however also has been identified to sequester CK1, a key component of the β-catenin destruction complex, that thereby prevents the degradation of β-catenin 10 . The notion that MDMX is overexpressed in the vast majority of AML patients (>90%), identified MDMX overexpression to accelerate AML formation in preleukemic Flt3 WT/ITD , URE -/and Tet2 -/transgenic mouse models that are used to model MDS/AML formation 10 .…”

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

“…MDMX however also has been identified to sequester CK1, a key component of the β-catenin destruction complex, that thereby prevents the degradation of β-catenin 10 . The notion that MDMX is overexpressed in the vast majority of AML patients (>90%), identified MDMX overexpression to accelerate AML formation in preleukemic Flt3 WT/ITD , URE -/and Tet2 -/transgenic mouse models that are used to model MDS/AML formation 10 . MDMX overexpression in HSC of transgenic mouse models and leukemic cell lines accordingly increases protein accumulation and nuclear translocation of βcatenin thereby altering gene expression, independent of p53 10 .…”

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

“…The notion that MDMX is overexpressed in the vast majority of AML patients (>90%), identified MDMX overexpression to accelerate AML formation in preleukemic Flt3 WT/ITD , URE -/and Tet2 -/transgenic mouse models that are used to model MDS/AML formation 10 . MDMX overexpression in HSC of transgenic mouse models and leukemic cell lines accordingly increases protein accumulation and nuclear translocation of βcatenin thereby altering gene expression, independent of p53 10 . HSCs obtained from high-risk MDS patients, displaying a high potential to develop AML, are also marked by increased MDMX expression and an active Canonical Wnt gene expression signature 10 .…”

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

“…MDMX overexpression in HSC of transgenic mouse models and leukemic cell lines accordingly increases protein accumulation and nuclear translocation of βcatenin thereby altering gene expression, independent of p53 10 . HSCs obtained from high-risk MDS patients, displaying a high potential to develop AML, are also marked by increased MDMX expression and an active Canonical Wnt gene expression signature 10 . Overall, this indicates that unrestrained activation of Wnt/β-catenin signaling may underlie dyserythropoiesis in MDS and to promote the transformation of MDS to AML (Figure 2).…”

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

“…Recently, chronic activation of β-catenin also has been assigned to drive transformation of MDS to acute myeloid leukemia (AML) 10,11 . Manipulation of β-catenin signaling may therefore offer a therapeutic treatment strategy to prevent or delay leukemia formation in MDS patients.…”

Section: Introductionmentioning

confidence: 99%

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Canonical Wnt: a safeguard and threat for erythropoiesis

Krimpenfort

Nethe

2021

Blood Advances

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Myeloid dysplastic syndrome (MDS) reflects a preleukemic BM disorder with limited treatment options and poor disease survival1. As only a minority of MDS patients is eligible to curative hematopoietic stem cell (HSC) transplantation, there is an urgent need to develop alternative treatment options. Chronic activation of Wnt/β-catenin has been implicated to underlie MDS formation and recently assigned to drive MDS transformation to acute myeloid leukemia (AML). Wnt/β-catenin signaling therefore may harbor a pharmaceutical target to treat MDS and/or prevent leukemia formation. However, targeting the Wnt/β-catenin pathway will also affect healthy hematopoiesis in MDS patients.The control of Wnt/β-catenin on healthy hematopoiesis is poorly understood. Whereas Wnt/β-catenin is dispensable for steady-state erythropoiesis, its activity is essential for stress erythropoiesis in response to BM injury and anemia. Manipulation of Wnt/β-catenin signaling in MDS may therefore deregulate stress erythropoiesis and even increase anemia severity. Here we provide a comprehensive overview of the most recent and established insights in the field to acquire more insight into the control of Wnt/β-catenin signaling on healthy and inefficient erythropoiesis as seen in MDS.

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Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

Section: Wnt/β-catenin Signaling Is Deregulated In Mdsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Canonical Wnt: a safeguard and threat for erythropoiesis

Krimpenfort

Nethe

2021

Blood Advances

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Oxidative stress is two‐sided in the treatment of acute myeloid leukemia

Fan,

Yang,

Yan

et al. 2024

Cancer Medicine

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IntroductionOxidative stress caused by elevated ROS, as a novel therapeutic mechanism, has been implicated in various tumors including AML. AML cells are chronically under oxidative stress, yet overreliance on ROS production makes tumor cells increasingly vulnerable to further damage. Reducing the cytotoxic effect of ROS on normal cells while killing leukemia stem cell (LSC) with high levels of reactive oxygen species is a new challenge for oxidative stress therapy in leukemia.MethodsBy searching literature databases, we summarized recent relevant studies. The relationship of ROS on AML genes, signaling pathways, and transcription factors, and the correlation of ROS with AML bone marrow microenvironment and autophagy were summarized. In addition, we summarize the current status of research on ROS and AML therapeutics. Finally, we discuss the research progress on redox resistance in AML.ResultsThis review discusses the evidence showing the link between redox reactions and the progression of AML and compiles the latest research findings that will facilitate future biological studies of redox effects associated with AML treatment.ConclusionWe believe that exploiting this unique oxidative stress property of AML cells may provide a new way to prevent relapse and drug resistance.

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Construction and experimental validation of a novel ferroptosis‐related gene signature for myelodysplastic syndromes

Zhu,

He,

Wei

et al. 2024

Immunity Inflam & Disease

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BackgroundMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by morphological abnormalities and peripheral blood cytopenias, carrying a risk of progression to acute myeloid leukemia. Although ferroptosis is a promising target for MDS treatment, the specific roles of ferroptosis‐related genes (FRGs) in MDS diagnosis have not been elucidated.MethodsMDS‐related microarray data were obtained from the Gene Expression Omnibus database. A comprehensive analysis of FRG expression levels in patients with MDS and controls was conducted, followed by the use of multiple machine learning methods to establish prediction models. The predictive ability of the optimal model was evaluated using nomogram analysis and an external data set. Functional analysis was applied to explore the underlying mechanisms. The mRNA levels of the model genes were verified in MDS clinical samples by quantitative real‐time polymerase chain reaction (qRT‐PCR).ResultsThe extreme gradient boosting model demonstrated the best performance, leading to the identification of a panel of six signature genes: SREBF1, PTPN6, PARP9, MAP3K11, MDM4, and EZH2. Receiver operating characteristic curves indicated that the model exhibited high accuracy in predicting MDS diagnosis, with area under the curve values of 0.989 and 0.962 for the training and validation cohorts, respectively. Functional analysis revealed significant associations between these genes and the infiltrating immune cells. The expression levels of these genes were successfully verified in MDS clinical samples.ConclusionOur study is the first to identify a novel model using FRGs to predict the risk of developing MDS. FRGs may be implicated in MDS pathogenesis through immune‐related pathways. These findings highlight the intricate correlation between ferroptosis and MDS, offering insights that may aid in identifying potential therapeutic targets for this debilitating disorder.

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MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Cited by 20 publications

References 84 publications

Canonical Wnt: a safeguard and threat for erythropoiesis

Canonical Wnt: a safeguard and threat for erythropoiesis

Oxidative stress is two‐sided in the treatment of acute myeloid leukemia

Construction and experimental validation of a novel ferroptosis‐related gene signature for myelodysplastic syndromes

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