MDM4 Overexpressed in Acute Myeloid Leukemia Patients with Complex Karyotype and Wild-Type TP53

Li, Li; Tan, Yanhong; Chen, Xiuhua; Xu, Zhifang; Yang, S.Y.; Ren, Fanggang; Guo, Haixiu; Wang, Xiaojuan; Chen, Yi; Li, Guoxia; Wang, Hongwei

doi:10.1371/journal.pone.0113088

Cited by 23 publications

(28 citation statements)

References 32 publications

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“…This result positions Mdmx protein as an important inhibitor of the p53 pathway especially in APL as well as in CN-AML. Our findings are in line with reports that revealed upregulated Mdmx protein in various human malignancies [32–35, 37, 38, 40] including AML with complex karyotype [41] and showed the ability of Mdmx to inhibit p53 activity in AML cell lines [135]. Here we present evidence for the link between Mdmx levels and functional inhibition of p53 in CN-AML and APL patients.…”

Section: Discussionsupporting

confidence: 93%

Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

et al. 2017

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BackgroundMechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood.MethodsWe performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes. We further investigated the functional status of the p53 pathway in cytogenetically normal AML (CN-AML) and Acute Promyelocytic Leukemia (APL) patients using bioinformatics, Real-Time PCR and immunohistochemistry.ResultsWe revealed significant and differential alterations of p53 pathway-related gene expression in most of the AML subtypes. We found that p53 pathway-related gene expression was not correlated with the accepted grouping of AML subtypes such as by cytogenetically-based prognosis, morphological stage or by the type of molecular mutation. Our bioinformatic analysis revealed that p53 is not functional in CN-AML and APL blasts at inducing its most important functional outcomes: cell cycle arrest, apoptosis, DNA repair and oxidative stress defense. We revealed transcriptional downregulation of important p53 acetyltransferases in both CN-AML and APL, accompanied by increased Mdmx protein expression and inadequate Chk2 protein activation.ConclusionsOur bioinformatic analysis demonstrated that p53 pathway is differentially inactivated in different AML subtypes. Focused gene and protein analysis of p53 pathway in CN-AML and APL patients imply that functional inactivation of p53 protein can be attributed to its impaired acetylation. Our analysis indicates the need in further accurate evaluation of p53 pathway functioning and regulation in distinct subtypes of AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0249-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

et al. 2017

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“…MDMX overexpression has been reported in a number of human cancers, including glioma, soft tissue sarcoma, melanoma, retinoblastoma, breast cancers, and hematological malignancies (24,27, 56–61). To compare MDMX expression in patients with different cancer types, we evaluated published gene expression data sets available in The Cancer Genome Atlas (TCGA).…”

Section: Resultsmentioning

confidence: 99%

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

et al. 2018

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The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these inter-actions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled a-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

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“…In the OCI/AML-2 cell line, it suppresses p53 activity, decreases its half-life, and promotes its cytoplasmic sequestration. 69,70 Notably, MDM2/4 overexpression in AML represents a molecular setup in which dysfunctional wtp53 is associated with unfavorable cytogenetics and poor prognosis, indicating the potential deleterious effect of nonmutational wtp53 dysfunction on genomic stability. 6,61,65 AML with NPM1 and FLT3 mutations NPM1/FLT3-mutated AML is often accompanied by wtp53 dysfunction due to several inactivating processes.…”

Section: Dysfunction In Aml and Its Clinical Relevance 703mentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

136

119

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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MDM4 Overexpressed in Acute Myeloid Leukemia Patients with Complex Karyotype and Wild-Type TP53

Cited by 23 publications

References 32 publications

Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

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