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Selected Works of Caleb Class
Article
Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes
Leukemia
  • Guillermo Montalban-Bravo, The University of Texas MD Anderson Cancer Center
  • Caleb Class, Butler University
  • Irene Ganan-Gomez, The University of Texas MD Anderson Cancer Center
  • Rashmi Kanagal-Shamanna, The University of Texas MD Anderson Cancer Center
  • Koji Sasaki, The University of Texas MD Anderson Cancer Center
  • Guillaume Richard-Carpentier, The University of Texas MD Anderson Cancer Center
  • Kiran Naqvi, The University of Texas MD Anderson Cancer Center
  • Yue Wei, The University of Texas MD Anderson Cancer Center
  • Hui Yang, The University of Texas MD Anderson Cancer Center
  • Kelly A. Soltysiak, The University of Texas MD Anderson Cancer Center
  • Kelly Chien, The University of Texas MD Anderson Cancer Center
  • Carlos Bueso-Ramos, The University of Texas MD Anderson Cancer Center
  • Kim-Anh Do, The University of Texas MD Anderson Cancer Center
  • Hagop Kantarjian, The University of Texas MD Anderson Cancer Center
  • Guillermo Garcia-Manero, The University of Texas MD Anderson Cancer Center
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Document Type
Article
Publication Date
3-1-2020
Disciplines
DOI
10.1038/s41375-019-0623-5
Additional Publication URL
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7056563&blobtype=pdf
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 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.

Rights

This is an archived version post-print version. It is reproduced here with permission from Leukemia and can be found here All Rights Reserved.

Citation Information
Guillermo Montalban-Bravo, Caleb Class, Irene Ganan-Gomez, Rashmi Kanagal-Shamanna, et al.. "Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes" Leukemia Vol. 34 Iss. 3 (2020) p. 872 - 881
Available at: http://works.bepress.com/caleb-class/24/