Tumor development is associated with the methylation of cytosine-guanine (CpG) islands. The occurrence of methylation requires several factors, such as DNA methylation systems and polycomb group (PcG) proteins. At present, novel drugs are needed for the treatment of chronic myeloid leukaemia (CML), particularly considering the current prognosis of CML. The methylation status of the Src homology 2 domain-containing tyrosine phosphatase 1 (SHP1) gene, a negative regulator of signal transduction, has been identified as being altered in numerous haematological malignancies. DNA methyltransferase 1 (DNMT1) and the PcG protein complex member enhancer of zeste homolog 2 (EZH2) participate in a number of gene methylation processes. The present study investigated the methylation status of the SHP1 gene in CML, and examined the association between DNMT1 and EZH2 activity and the SHP1 gene methylation status to develop novel strategies for the treatment of CML. The results revealed that SHP1 gene methylation status was altered during the progression of CML. These data indicated that SHP1 gene methylation is associated with the progression of this disease. The associations of DNMT1 and EZH2 activities with the methylation status of the SHP1 gene were additionally investigated via chromatin immunoprecipitation. DNMT1 and EZH2 were revealed to be bound to the promoter region of the SHP1 gene, and were involved in the process of SHP1 methylation. Furthermore, DNMT1 and EZH2 were associated with disease progression. Thus, the findings of the present study suggest a new target for the treatment of CML, particularly for future drug development.