The signal regulatory protein (SIRP) α1 is a cell surface receptor expressed predominantly in monocytes, granulocytes, dendritic cells, as well as hematopoietic stem cells. In contrast, SIRPα1 expression is significantly reduced in the majority of myeloid malignancies. SIRPα1 is a negative regulator of signaling and its reduced expression is considered to play a role in the pathogenesis of these diseases through aberrant signaling. To identify SIRPα1 downstream target genes, we established SIRP α1-knockdown chronic myeloid leukemia K562 (K562SIRPα1KD) cells expressing reduced levels of SIRPα1 by stably transfecting SIRPα1 siRNAs. Microarray analysis demonstrated that several genes, including β-catenin, were significantly induced in K562SIRPα1KD cells. Real-time PCR and Western blot analyses, confirmed the induction of this gene. Phosphorylation of Ser9 of glycogen synthesis kinase (GSK) -3β, results in the inactivation of GSK-3β, leading to the induction of β-catenin. We found significant phosphorylation of extracellular signal-regulated kinase (ERK), Akt, as well as of GSK-3β-Ser9, which may play a role in the up-regulation of β-catenin in K562SIRPα1KD cells. To our knowledge, this is a first report demonstrating the relationships between SIRPα1 and β-catenin in leukemia cells.