Down-regulation of protein tyrosine phosphatase gamma (PTPRG) in chronic myeloid leukemia (CML)

Background. Chronic Myelogenous Leukemia (CML) is the most common myeloproliferative disease while Receptor Protein Tyosine Phosphatase Gamma (PTPRG) has been implicated as a candidate tumor suppressor gene being its expression reduced in various neoplasms and somatic mutation detected in colon cancer. PTPRG regulates murine hemopoiesis and is expressed in specific hematopoietic lineages including CD34+ cells. Aims. Explore the possibility that PTPRG could be involved in the pathogenesis of CML. Methods. mRNA and protein levels were measured in cell lines, bone marrow and peripheral blood cells by real-time PCR and flow cytometry using a newly developed antibody specific for the extracellular domain of PTPRG. Proliferation, clonogenic and xenografting assays were used to study the effect of PTPRG cDNA transfection in CML cell lines. Results. We found that PTPRG expression was undetectable in two of four CML cell lines analyzed. Its loss correlates with higher clonogenicity and proliferation capabilities, while reexpression inhibits both parameters, reduces tyrosine phosphorylation and induces myeloid differentiation in stably transfected K562 cells. The oncosuppressive and differentiation-inducing effect of PTPRG was confirmed in vivo after xenotransplantation in a nude mice model. PTPRG is down regulated at mRNA and protein levels in leukocytes of CML (but not of chronic lymphocytic leukemia-CLL) patients in both peripheral blood and bone marrow, including CD34+ cells, and is reexpressed following molecular remission of the disease. Conclusions. Loss of PTPRG expression is associated to the pathogenesis of CML and designate PTPRG as a new pharmacological target. Measurement of PTPRG expression levels might find clinical application for confirming diagnosis and for following progression of disease and treatment.