BACKGROUND: Myelodysplastic syndromes (MDS) is defined as heterogenous disease, it contains heterogenous leukemic stem cells with various degree of cell differentiation. The perturbation of genes involved in myeloid progenitor cell growth, differentiation and proliferation lead to morphologic dysplasia, maturation arrest, ineffective hematopoiesis hence the cytopenias and propensity to develop into acute myeloid leukemia (AML). Heterogeneous subsets of MDS patients have been defined by their clinical and biologic abnormalities. These different features lead to the development of different prognostic system; however, these approaches are limited in predicting clinical course, and management of patients remains challenging given the uncertainty of the time course of disease progression. It is of importance to identify transcriptomic marker causing maturational and differentiation arrest which could help in understanding the pathogenesis of disease. METHODS AND RESULTS: We have studied differential gene expression profiles (GEPs) in CD34 + marrow cells from myelodysplastic syndrome (MDS) patients (n = 14) and control CD34 + cells using Affymetrix Human Clariom S microarray with 20,000 well annotated genes. We found 4165 genes significantly (p < 0.05) differentially expressed in MDS. Using stringent bioinformatics analyses, we were able to identify few genes (MAPK8, JUNB, mTOR) which were differentially upregulated i.e. 5.39, 73.61 and 2.7 fold change observed in MDS than control and also validated (n = 60) these genes by RT - qPCR. Kaplan - Meier survival analysis indicated that MAPK8 and JUNB could be poor prognostic marker as patients with increased expression showed poor survival, whereas surprisingly mTOR increased expression proved to be good prognostic marker. The correlation analysis showed that the level of gene (MAPK8, JUNB, mTOR) expression was significantly (p ≤ 0.05) associated with frequency of genetic lesions. Interestingly the increased expression of MAPK8 was significantly accompanied with ASXL1 gene mutation. CONCLUSION: Our study showed an elevation of TNF and AMPK signalling pathways in MDS. TNF signalling might be mediating the proliferative advantage to myeloid clonal cells (mutation carrying cells) over normal cells, whereas, AMPK signalling could be acting as protector against it (favouring normal cells). Hence it would be interesting to explore the functions and pathways associated with mTOR, AMPK, MAPK8 and JUNB in myelopoiesis related diseases like MDS.