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

Guillermo Montalban-Bravo, Caleb A. Class, Irene Ganan-Gomez, Rashmi Kanagal-Shamanna, Koji Sasaki, Guillaume Richard-Carpentier, Kiran Naqvi, Yue Wei, Hui Yang, Kelly A. Soltysiak, Kelly Chien, Carlos Bueso-Ramos, Kim Anh Do, Hagop Kantarjian, Guillermo Garcia-Manero

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)872-881
Number of pages10
JournalLeukemia
Volume34
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Biostatistics Resource Group

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