Back to Search
Start Over
Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes.
- Source :
-
Leukemia [Leukemia] 2020 Mar; Vol. 34 (3), pp. 872-881. Date of Electronic Publication: 2019 Nov 12. - Publication Year :
- 2020
-
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.
- Subjects :
- Aged
Antigens, CD34 metabolism
Bone Marrow metabolism
Disease Progression
Female
Humans
Inflammation
Leukemia, Myelomonocytic, Chronic diagnosis
Leukemia, Myelomonocytic, Chronic metabolism
Male
Middle Aged
Myelodysplastic Syndromes metabolism
Phenotype
Prognosis
Protein Kinases metabolism
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Myelodysplastic Syndromes diagnosis
Necroptosis
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 34
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 31719677
- Full Text :
- https://doi.org/10.1038/s41375-019-0623-5