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MYELODYSPLASTIC NEOPLASM

Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target

Leukemia volume 37, pages 2507–2511 (2023)Cite this article

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Myelodysplastic syndromes (MDS) are a clinically and molecularly heterogeneous group of malignant hematopoietic stem cell (HSC) neoplasms [1, 2]. Hypomethylating agents (HMAs) and allogeneic stem cell transplant (HSCT) remain the only disease-modifying therapies for MDS, but HMA response rates are unsatisfactory and unpredictable [3] and HSCT confers risk of substantial non-relapse morbidity and mortality.

Dysfunction of the tumor suppressor p53 defines an especially aggressive subset of MDS with resistance to current therapies and rapid progression to acute myeloid leukemia (AML) [4]. In steady state degradation of wild-type (WT) p53 is mediated by the MDM2/MDMX complex, thereby regulating activation of p53 target genes. Interestingly, MDMX, which prevents p53 transactivation, is overexpressed in a proportion of patients with de novo AML suggesting a loss of p53 function even in p53 WT patients [5]. Recently, MDMX overexpression was shown to cause transition from preleukemia to overt AML in murine models via activation of Wnt/β-Catenin signaling in a p53-independent context and was associated with progression from MDS to AML [6]. The clinical relevance of MDMX expression in MDS patients is, however, unknown.

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Fig. 1: Clinical and prognostic relavance of MDMX expression in patients with primary myelodysplastic syndromes.
Fig. 2: Association of higher MDMX expression with HMA resistance and inferior survival in MDS and the therapeutic implication of MDMX modulation.

Data availability

The datasets generated during and/or analyzed during the current study can be accessed through Gene Expression Omnibus database (accession number GSE223305, GSE97064, and GSE114922) or on reasonable request from the corresponding author.

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Acknowledgements

We acknowledge the service provided by the Department of Laboratory Medicine, Department of Medical Research, Department of Pathology, and Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital. YHW, KG, KB, and DW are supported by grants from The Oglesby Charitable Trust.

Funding

The work was supported by grants from Ministry of Science and Technology, Taiwan, project number: MOST 109-2314-B-002-221, 109-2314-B-002-222, 111-2314-B-002-280; and Taiwan Ministry of Health and Welfare, project number: MOHW109-TDU-B-211-134009. FMRA and BW are supported by Cancer Research UK grant number C5759/A27412. BW was also supported by a John Goldman Fellowship from Leukaemia UK (2020/JGF/005) and by the Lady Tata Memorial Trust. The Epigenetics of Haematopoiesis Laboratory (YHW, DHW, KB, KG) is core funded by a grant from The Oglesby Charitable Trust. DHW is also supported by grants from Cancer Research UK (RCCASF-Nov22/100001) and The University of Manchester Sybil Mary Pilkington Leukaemia Research Fellowship.

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Authors and Affiliations

  1. Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan

    Yu-Hung Wang, Chien-Chin Lin, Chi-Yuan Yao, Hsin-An Hou, Wen-Chien Chou & Hwei-Fang Tien

  2. Epigenetics Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, UK

    Yu-Hung Wang, Kristian Gurashi, Kiran Batta & Daniel H. Wiseman

  3. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Chien-Chin Lin, Chi-Yuan Yao & Wen-Chien Chou

  4. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Manchester, UK

    Bettina Wingelhofer & Fabio M. R. Amaral

  5. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Hsin Ting Hsieh & Ming Chih Liu

  6. Department of Internal Medicine, Fra-Eastern Memorial Hospital, New Taipei City, Taiwan

    Hwei-Fang Tien

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  1. Yu-Hung Wang
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Contributions

YHW was responsible for data collection and management, statistical analysis, interpretation, visualization, literature research, and manuscript writing; CYY, KG, and FA assisted in bioinformatic analysis; BW, KB, and DW assisted with drug tests, data interpretation and manuscript preparation/revision; HTH and MCL helped with sample processing, HAH and WCC were responsible for data collection and management; and CCL and HFT conceived and coordinated the study and revised the manuscript.

Corresponding authors

Correspondence to Chien-Chin Lin or Hwei-Fang Tien.

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The authors declare no competing interests.

Ethics statement

The National Taiwan University Hospital Research Ethics Committee approved the study (#201709072RINC). Informed consent was obtained in accordance with the Helsinki Declaration. Cryopreserved bone marrow samples for ex vivo drug tests were obtained from the Manchester Cancer Research Centre Tissue Biobank with South Manchester Research Ethics Committee approval.

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Wang, YH., Lin, CC., Gurashi, K. et al. Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target. Leukemia 37, 2507–2511 (2023). https://doi.org/10.1038/s41375-023-02044-2

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