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

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 to 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 1g/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 non-responders (−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 indicates that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS.