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Updated: Oct 19, 2025
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Programmed necroptosis is upregulated in low-grade myelodysplastic syndromes and may play a role in the pathogenesis
Jing Zou1, Qiong Shi1, Heidi Chen2
1Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Abstract:
Myelodysplastic syndrome (MDS) is characterized by persistent cytopenias and evidence of morphologic dysplasia in the bone marrow (BM). Excessive hematopoietic programmed cell death (PCD) and inflammation have been observed in the bone marrow of patients with MDS, and are thought to play a significant role in the pathogenesis of the disease. Necroptosis is a major pathway of PCD that incites inflammation; however, the role of necroptosis in human MDS has not been extensively investigated. To assess PCD status in newly diagnosed MDS, we performed immunofluorescence staining with computational image analysis of formalin-fixed, paraffin-embedded BM core biopsies using cleaved caspase-3 (apoptosis marker) and necroptosis markers (receptor-interacting serine/threonine-protein kinase 1 [RIPK1], phospho-mixed lineage kinase domain-like protein [pMLKL]). Patients with MDS, but not controls without MDS or patients with de novo acute myeloid leukemia, had significantly increased expression of RIPK1 and pMLKL but not cleaved caspase-3, which was most evident in morphologically low-grade MDS (<5% BM blasts) and in MDS with low International Prognostic Scoring System risk score. RIPK1 expression highly correlated with the distribution of CD71+ erythroid precursors but not with CD34+ blast cells. We found that necroptosis is upregulated in early/low-grade MDS relative to control participants, warranting further study to define the role of necroptosis in the pathogenesis of MDS and as a potential biomarker for the diagnosis of low-grade MDS.
Insights
Necroptosis, a cell death pathway, is elevated in early myelodysplastic syndromes (MDS). This finding suggests necroptosis may play a role in MDS pathogenesis and could serve as a diagnostic biomarker for low-grade MDS.
Area of Science:
- Hematology
- Cell Biology
- Immunology
Background:
- Myelodysplastic syndrome (MDS) involves persistent low blood counts and bone marrow dysplasia.
- Excessive hematopoietic programmed cell death (PCD) and inflammation are implicated in MDS pathogenesis.
- Necroptosis, a pro-inflammatory PCD pathway, has not been well-studied in human MDS.
Purpose of the Study:
- To investigate the status of PCD, specifically necroptosis, in newly diagnosed MDS.
- To evaluate necroptosis markers in relation to MDS grade and prognostic scores.
- To explore the potential of necroptosis as a biomarker for low-grade MDS.
Main Methods:
- Immunofluorescence staining of bone marrow biopsies from MDS patients and controls.
- Computational image analysis to quantify apoptosis (cleaved caspase-3) and necroptosis markers (RIPK1, pMLKL).
- Correlation analysis of necroptosis markers with MDS characteristics like blast percentage and International Prognostic Scoring System (IPSS) score.
Main Results:
- MDS patients showed significantly increased RIPK1 and pMLKL expression compared to controls and acute myeloid leukemia patients.
- Elevated necroptosis markers were not associated with increased apoptosis (cleaved caspase-3).
- Increased RIPK1 expression correlated with erythroid precursors (CD71+) but not with blast cells (CD34+).
- Necroptosis upregulation was most pronounced in low-grade MDS (<5% BM blasts) and low IPSS risk MDS.
Conclusions:
- Necroptosis is upregulated in early-stage myelodysplastic syndromes.
- The findings suggest a potential role for necroptosis in MDS pathogenesis.
- Necroptosis markers may serve as diagnostic biomarkers for low-grade MDS, warranting further investigation.
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