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Protein Tyrosine Phosphatase Receptor Gamma as Potential Therapeutic Target for Chronic Myeloid Leukemia Patients.

ABSTRACT: The worldwide CML incidence expects 100,000 patients every year thus representing a substantial health burden. A year 2000 is notable year, where Tyrosine kinase inhibitors (TKIs) had been introduced to the CML treatment plan. However, despite the dramatically reduce in mortality rate of CML patients due to TKIs, still over 25% of CML patients need to switch TKIs at least once during treatment timeline for many reasons. On the other hand, PTPRG behave as a tumor suppressor gene in different neoplasms and is strongly down-regulated in CML patients. We discussed briefly in series of articles the possible reasons of it is down regulation. Here, we discuss its role as potential therapeutic target in treatment plan.

SUBMITTER: Ismail MA

PROVIDER: S-EPMC9677154 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature

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Protein Tyrosine Phosphatase Receptor Gamma as Potential Therapeutic Target for Chronic Myeloid Leukemia Patients.

Ismail Mohamed A MA Sorio Claudio C Al-Dewik Nader N

Cancer control : journal of the Moffitt Cancer Center 20220101

The worldwide CML incidence expects 100,000 patients every year thus representing a substantial health burden. A year 2000 is notable year, where Tyrosine kinase inhibitors (TKIs) had been introduced to the CML treatment plan. However, despite the dramatically reduce in mortality rate of CML patients due to TKIs, still over 25% of CML patients need to switch TKIs at least once during treatment timeline for many reasons. On the other hand, <i>PTPRG</i> behave as a tumor suppressor gene in differe ...[more]

PMID: 36382578

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Project description:BackgroundProtein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients.MethodsTPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry.ResultsCo-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells.ConclusionsThe availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.

Project description:BACKGROUND: Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. METHODS: To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. RESULTS: In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. CONCLUSIONS: RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.

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Protein Tyrosine Phosphatase Receptor Gamma as Potential Therapeutic Target for Chronic Myeloid Leukemia Patients.

Publications

Protein Tyrosine Phosphatase Receptor Gamma as Potential Therapeutic Target for Chronic Myeloid Leukemia Patients.

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