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

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.

SUBMITTER: Montalban-Bravo G

PROVIDER: S-EPMC7056563 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Montalban-Bravo Guillermo G Class Caleb A CA Ganan-Gomez Irene I Kanagal-Shamanna Rashmi R Sasaki Koji K Richard-Carpentier Guillaume G Naqvi Kiran K Wei Yue Y Yang Hui H Soltysiak Kelly A KA Chien Kelly K Bueso-Ramos Carlos C Do Kim-Anh KA Kantarjian Hagop H Garcia-Manero Guillermo G

Leukemia 20191112 3

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 ...[more]

PMID: 31719677

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Project description:BackgroundMyelodysplastic syndromes (MDS) are heterogeneous and clonal hematological disorders. The role and mechanism of necroptosis in MDS remain poorly understood.MethodsmRNA expression profiles and single-cell RNA-sequencing (scRNA-seq) data were sourced from the GEO database. ScRNA-seq data were processed using the "Seurat" package. After cell annotation, necroptosis-related scores (NRscores) for each cell were calculated using the "UCell" package. Differentially expressed genes (DEGs) and their associated biological functions in NRscore-related cell populations were identified. Additionally, DEGs and necroptosis-related genes (DE-NRGs) between MDS patients and healthy controls were identified. Consensus clustering was employed to classify MDS patients into distinct subclusters based on DE-NRGs. The biological functions and immune characteristics of these classifications were analyzed. Prognostic gene signatures were determined using LASSO and SVM-RFE analyses, and a nomogram was constructed based on the prognostic gene signature.ResultsA total of 12 cell types were identified in MDS and healthy controls. NRscore was found to be elevated in monocytes and common lymphoid precursors (CLPs). Enrichment analysis revealed that monocytes and CLPs with high NRscore were associated with mitochondria-related and immune-related pathways. Eleven DEGs in monocytes and CLPs between MDS patients and healthy controls were identified. Additionally, 13 DE-NRGs were identified from 951 DEGs between MDS and healthy controls. MDS patients were classified into two distinct subclusters based on these 13 DE-NRGs, revealing several immune-related processes and signaling pathways. Differences in immune subpopulations between the two subclusters were observed. A necroptosis-related diagnostic gene signature (IRF9, PLA2G4A, MLKL, BAX, JAK2, and STAT3) was identified as predictive of MDS prevalence.ConclusionNecroptosis plays a role in MDS progression by inducing inflammation. A novel necroptotic gene signature has been developed to distinguish and diagnose MDS at early stages of the disease.

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

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

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