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Myelodysplastic syndrome

Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes

Leukemia volume 34, pages 872–881 (2020)Cite this article

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Abstract

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n = 46) or after (n = 18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-Seq. Compared with healthy controls, expression levels of MLKL (CMML: 2.09 log2FC, p = 0.0013; MDS: 1.89 log2FC, p = 0.003), but not RIPK1 or RIPK3, were significantly upregulated. Higher expression levels of MLKL were associated with lower hemoglobin levels at diagnosis (−0.19 log2FC per 1 g/dL increase of Hgb, p = 0.03). Significant reduction in MLKL levels was observed after HMA therapy (−1.06 log2FC, p = 0.05) particularly among nonresponders (−2.89 log2FC, p = 0.06). Higher RIPK1 expression was associated with shorter survival (HR 1.92, 95% CI 1.00–3.67, p = 0.049 by Cox proportional hazards). This data provides further support for a role of necroptosis in MDS, and potentially response to HMAs and prognosis. This data also indicate that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672 and the University of Texas MD Anderson MDS/AML Moon Shot.

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  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Guillermo Montalban-Bravo, Irene Ganan-Gomez, Koji Sasaki, Guillaume Richard-Carpentier, Kiran Naqvi, Yue Wei, Hui Yang, Kelly A. Soltysiak, Kelly Chien, Hagop Kantarjian & Guillermo Garcia-Manero

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Caleb A. Class & Kim-Anh Do

  3. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Rashmi Kanagal-Shamanna & Carlos Bueso-Ramos

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Conflict of interest

HK declares research support and an advisory role with Actinium, and research support from AbbVie, Agio, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. GG-M declares research support and an advisory role with Amphivena, Astex, and Celgene, and research support from AbbVie, H3 Biomedicine, Helsin, Onconova, Merck, and Novartis. The other authors declare that they have no conflict of interest.

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Supplementary Information for Transcriptomic analysis of necroptosome components suggest implications of necroptosis in disease progression and prognosis of patients with myelodysplastic syndromes

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Montalban-Bravo, G., Class, C.A., Ganan-Gomez, I. et al. Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes. Leukemia 34, 872–881 (2020). https://doi.org/10.1038/s41375-019-0623-5

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