Protein Tyrosine Phosphatase Receptor Type γ Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia

Abstract

Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34 + cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34 + cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. Cancer Res; 70(21); 8896-906. ©2010 AACR.

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

“…The antigen is a glycoprotein, the epitopes of which can greatly influence the capability of the resulting antibodies to recognize the native antigen. We previously evaluated the capability of affinity-purified TPγ B9-2 to recognize the full-length protein by immunoprecipitation in the K562 cell line transfected with PTPRG cDNA [8]. Glioblastoma expresses one of the highest levels of PTPRG [19].…”

“…Forced overexpression of PTPRG led to reduced tyrosine phosphorylation, decreased clonogenic capability, and induction of apoptosis in CML cells. In the same study, we have shown that BCR-ABL1, the key deregulated kinase in CML, is a biochemical substrate for PTPRG [8]. Two epitope-specific antisera against the extracellular domain (ECD) of PTPRG have previously been developed from rabbit [9] and chicken [10].…”

Protein Tyrosine Phosphatase Receptor Type γ Is a JAK Phosphatase and Negatively Regulates Leukocyte Integrin Activation

“…Taken together, these observations suggest that KIT, ABL1, and BTK may be involved in LFA-1 affinity modulation by chemoattractants, perhaps concurrently cooperating with JAKs. Interestingly, ABL1 was already shown to be a direct PTPRG target (45). A role for these kinases in LFA-1 affinity modulation is unknown, and it will be of interest to investigate their involvement in leukocyte trafficking.…”

“…Notably, many neoplastic cells modulate the expression of PTPRG (19). In this context, PTPRG has been recently proposed as a tumor suppressor gene involved in the pathogenesis of CML (45). Furthermore, KIT and ABL1, PTPRG targets, are oncogenes.…”

Induction of Apoptosis and Antitumor Activity by Stichoposide D through the Generation of Ceramide in Human Leukemia Cells

“…만성 골수성 백혈병은 모든 백혈 병의 약 15∼20%를 차지하고 100,000명에 1∼1.5명의 빈도로 발생한다고 보고되었다 [4]. 만성 골수성 백혈병은 무기력, 체 중 감소, 출혈, 식은 땀, 빈혈, 및 비장 비대증(splenomegaly)을 포함하는 증상이 있음에도 불구하고, 환자의 약 50%는 증상이 없어 혈액 검사로 진단되는 경우가 많다 [15].…”