The last decade has witnessed an explosion of knowledge on microRNAs (miRNAs) and their functions in both normal and abnormal physiological contexts. Myeloid leukaemias are extremely diverse and complex diseases. Their occurrence has been demonstrated to be correlated with miRNAs expression aberrations. In order to identify miRNAs that have main role in regulation of OSKM factors and Tp53, here we present an in-depth analysis of miRNomes in human Acute Myeloid Leukaemia (AML) cell line, HL-60 and one human Chronic Myeloid Leukaemia (CML) cell line, K562, via high-throughput sequencing. Small RNA sequences obtained by high throughput sequencing of normal peripheral blood samples and myeloid cell lines K562 and HL60 were analysed to identify known miRNAs expression patterns. Target genes of the miRNAs were also identified using miRTarBase database. All the unique transcripts were used for the functional annotation exploiting the blast2go functional annotation tool. Our miRNome analysis identified about 50 miRNAs with complementary sites within target mRNAs of OSKM and Tp53 transcription factors. They included miR-335, miR-126, miR-34c, miR-21, miR-340, miR-10b, miR-25, miR-130a, miR-103a and miR-107. They were differentially expressed in myeloid cell lines. The unique expression patterns of miRNAs in cell lines confirm cell type and context dependent expression of miRNAs. Moreover, we identified a number of miRNAs that were differentially expressed in myeloid cell lines acting as regulators of OSKM and Tp53 transcription factor genes. These findings suggest the existence of complicated crosstalk mechanisms between identified differentially expressed miRNAs and these factors. This underlines the importance and complexity of the functional roles of dysregulated miRNAs in leukemogenesis. That act by disturbing some essential networks related to proliferation, differentiation, apoptosis, signal transduction, cell division and tumor suppression.