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Transcription factor stem cell leukemia (SCL), also known as the T-cell acute lymphocytic leukemia 1 (TAL1), plays a key role in the regulation of hematopoiesis, but the molecular mechanisms are not well understood. The aim of the present study is to elucidate the effects of the epidermal growth factor receptor (EGFR) signal pathways underlying the biologic activity of SCL/TAL1 on normal hematopoietic development. Lentiviral vectors with up or down-regulation of SCL/TAL1 were transfected into umbilical cord blood CD34 stem cells. EGFR signaling pathways (including MEK/ERK and Akt/mTOR) and surface hematopoietic markers were analyzed in the process of hematopoietic differentiation. The data revealed that up or down-regulation of SCL/TAL1 gene was accompanied positively by the expressions of p-MEK and p-ERK1/2 protein, but the changes of Akt/mTOR were unobvious. MEK/ERK inhibitor U0126 and SCL/TAL1 down-regulation showed similar inhibitory effects on erythroid, myeloid, and megakaryoid differentiation. However, Akt/mTOR pathway altered insignificantly. MEK/ERK inhibitor U0126 could not affect the expression of SCL/TAL1 mRNA or protein. Taken together, these findings fully illustrated that SCL/TAL1 is located in the up-stream of MEK/ERK pathway and partially regulates hematopoiesis by modulating the phosphorylation level of the key proteins in MEK/ERK pathway.