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Overexpression of Pro-Inflammatory Cytokines in Myelodysplastic Syndrome (MDS-RA)

Natarajan Venkateswaran, Perumal Venkatachalam, Venkatesan Vettriselvi, Solomon FD Paul, Usha Nair, Margaret Chellaraj and Dominic F Joseph

Background: Myelodysplasia comprises a heterogenous group of disorder characterized by ineffective hematopoiesis and extensive apoptosis of hematopoietic cells. Although previous studies revealed few cytogenetic and molecular abnormalities, the underlying defect in the molecular pathway for extensive apoptosis and dysplasia observed in the disease is yet to be identified. This study aims to evaluate the pro-inflammatory cytokines and transcription factors levels in the refractory anemia subset of myelodysplasia (MDS-RA). The study evaluated bone marrow aspirates from 35 MDS-RA and 10 leukemic cases. All samples were analyzed for the rate of apoptosis, levels of various pro-inflammatory cytokines such as TNF-α, TNF receptors, TGF-β, Fas, IFN-γ and transcription factor NFκB that moderates the apoptotic pathway, were estimated by quantitative PCR. Results: Increased apoptosis in conjunction with significantly elevated cytokines levels of all the three subtypes of TGF-β1, TGF-β2, TGF-β3, TNF-α in MDS-RA samples. TNFR1 and TNFR2 (p<0.05) expression were significantly increased in MDS-RA than the leukemia group along with the Fas and INF-γ. Expressions of transcription factor subtypes NFκB1, NFκB2 and NFκB3 were observed significantly high (p<0.05) in MDS-RA compared to leukemia group. Conclusion: The findings of the study imply a defective signaling of pro-inflammatory cytokines and transcriptional factor NFκB pathway attributing to extensive apoptosis in early MDS. Highly deregulated cytokine signaling in the bone marrow samples of MDS contributes to the extensive apoptosis and also, a possible hematopoietic arrest resulting in refractory anemia. In addition, the dysregulation of cytokine expression contributes to genomic alteration resulting in MDS progression to acute myeloid leukemia (AML).