TY - JOUR
T1 - Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes
AU - Montalban-Bravo, Guillermo
AU - Class, Caleb A.
AU - Ganan-Gomez, Irene
AU - Kanagal-Shamanna, Rashmi
AU - Sasaki, Koji
AU - Richard-Carpentier, Guillaume
AU - Naqvi, Kiran
AU - Wei, Yue
AU - Yang, Hui
AU - Soltysiak, Kelly A.
AU - Chien, Kelly
AU - Bueso-Ramos, Carlos
AU - Do, Kim Anh
AU - Kantarjian, Hagop
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41375-019-0623-5
DO - 10.1038/s41375-019-0623-5
M3 - Article
C2 - 31719677
AN - SCOPUS:85074994116
SN - 0887-6924
VL - 34
SP - 872
EP - 881
JO - Leukemia
JF - Leukemia
IS - 3
ER -