Deletion of the Protein Tyrosine Phosphatase Gene PTPN2 in T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 141-141
Author(s):  
Maria Kleppe ◽  
Idoya Lahortiga ◽  
Tiama El Chaar ◽  
Kim De Keersmaecker ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Aberrant Expression ◽  
Protein Tyrosine ◽  
Knock Down

Abstract Abstract 141 Introduction: T-cell lymphoblastic leukemia (T-ALL) arises from clonal expansion of a lymphoid progenitor that has undergone stepwise alteration at distinct stages of differentiation. It is suggested that a set of cooperative mutations that affect different pathways are required before thymocytes become fully malignant. Despite major improvements in our understanding of the molecular genetics of T-ALL, the underlying mechanisms that lead to the abnormal proliferation and enhanced survival of the leukemic cells remain largely unknown. Results: Array CGH analysis revealed an acquired homozygous microdeletion at chromosome 18p11 in 6 % of T-ALL cases. The deleted region was only 125 kb in size and restricted to the PTPN2 (protein tyrosine phosphatase, non-receptor type 2) locus. PTPN2 encodes an intracellular non-transmembrane tyrosine-specific phosphatase that functions as a negative regulator of a variety of signaling proteins including several members of the janus kinase (JAK) and of signal transducer and activator of transcription (STAT) families, growth factor receptors and SRC family kinases. Homozygous deletion of PTPN2 was specifically found in cases with aberrant expression of the TLX1 transcription factor, with two cases also harboring the NUP214-ABL1 fusion. Analysis of additional TLX1 positive cases by quantitative PCR identified loss of one copy of PTPN2 in 5 out of 20 cases. No mutations were detected in the coding region of PTPN2. To determine the effect of loss of PTPN2 in T-cells, we downregulated the expression of PTPN2 using RNAi technology. siRNA mediated knock-down of PTPN2 affected activation of JAK1 associated cytokine receptors implicated in T-cell development. Ligand stimulation of IL7 and interferon gamma receptor resulted in an augmented and prolonged phosphorylation of JAK1 as well as downstream targets STAT1 and STAT5 in T-ALL cell lines with knock-down of PTPN2. In addition, knock- down of Ptpn2 sensitized the pro B-cell line Ba/F3 to transformation by wild type JAK1 confirming a clear relationship between loss of PTPN2 and JAK1 activation. Knock-down of PTPN2 expression also provided a proliferative advantage and reduced sensitivity to kinase inhibitors in lymphoblastic leukemia cell lines HSB-2 and ALL-SIL. Conclusion: In conclusion, our data provide genetic and functional evidence for a tumor suppressor role of PTPN2 in T-ALL and warrant testing of JAK inhibitors for the treatment of this specific subset of T-ALLs as well as further analysis of a potential negative impact of loss of PTPN2 on responsiveness to anti-cancer treatments. Disclosures: Ferrando: Merck, Pfizer: Research Funding.

scholarly journals The Role of Protein Tyrosine Phosphatase PTP4A3 in T-Cell Acute Lymphoblastic Leukemia Progression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2539-2539
Author(s):  
Min Wei ◽  
Jessica Blackburn
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Phosphatase ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Causative Role ◽  
Protein Tyrosine ◽  
Cell Acute Lymphoblastic Leukemia

The tyrosine protein tyrosine phosphatase PTP4A3 has been extensively reported to play a causative role in numerous cancers, including several types of acute leukemia. We found PTP4A3 to be highly expressed in T-cell Acute Lymphoblastic Leukemia samples, and show that PTP4A3 accelerates T-ALL onset and increases the invasive ability of T-ALL cells in a zebrafish model, and is required for T-ALL engraftment and progression in mouse xenograft. Our in vitro studies showed that PTP43A3 enhances T-ALL migration, in part via modulation of SRC signaling. However, whether SRC is a direct substrate of PTP4A3, and whether the phosphatase activity of PTP4A3 actually plays a role in T-ALL or other types of leukemia progression is unknown and remains a major question in the field. We used a BioID-based proximity labeling approach combined with PTP4A3 substrate trapping mutant pull down assay to capture the PTP4A3 substrates candidates. BioID, a biotin ligase, was fused to PTP4A3 to generate a Biotin-PTP4A3 (BP) fusion protein. The overexpression of BP in T-ALL cell lines led to biotin modification of 288 PTP4A3 proximal proteins, including the potential direct PTP4A3 substrates. PANTHER pathway analysis showed that PTP4A3 interacting proteins are largely clustered in the T-cell activation, PDGF signaling, and angiogenesis. We are in process of validating potential substrates using immunoprecipitation and phosphoenrichement assays. Finally, we are using a novel zebrafish Myc+PTP4A3 induced T-ALL model to assess the function of PTP4A3 in leukemia progression. We have created several PTP4A3 protein mutants, including a phosphatase-dead mutant, a mutant unable to bind magnesium transporter, and a prenylation deficient mutant, and are in process of assessing the effects of these mutants in T-ALL onset and progression in our in vivo model. In total, these studies will allow us to better understand function of PTP4A3 in T-ALL progression, and may provide a strong rationale for the development of PTP4A3 inhibitors for use in leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals T-Cell Protein Tyrosine Phosphatase (Tcptp) Is a Negative Regulator of Colony-Stimulating Factor 1 Signaling and Macrophage Differentiation

2006 ◽  
Vol 26 (11) ◽  
pp. 4149-4160 ◽  
Author(s):  
Paul D. Simoncic ◽  
Annie Bourdeau ◽  
Ailsa Lee-Loy ◽  
Larry R. Rohrschneider ◽  
Michel L. Tremblay ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Mononuclear Phagocyte ◽  
Negative Regulator ◽  
Cell Protein ◽  
Colony Stimulating Factor ◽  
Protein Tyrosine ◽  
Systemic Inflammatory Disease ◽  
Stimulating Factor

ABSTRACT Mice null for the T-cell protein tyrosine phosphatase (Tcptp−/−) die shortly after birth due to complications arising from the development of a systemic inflammatory disease. It was originally reported that Tcptp−/− mice have increased numbers of macrophages in the spleen; however, the mechanism underlying the aberrant growth and differentiation of macrophages in Tcptp−/− mice is not known. We have identified Tcptp as an important regulator of colony-stimulating factor 1 (CSF-1) signaling and mononuclear phagocyte development. The number of CSF-1-dependent CFU is increased in Tcptp−/− bone marrow. Tcptp−/− mice also have increased numbers of granulocyte-macrophage precursors (GMP), and these Tcptp−/− GMP yield more macrophage colonies in response to CSF-1 relative to wild-type cells. Furthermore, we have identified the CSF-1 receptor (CSF-1R) as a physiological target of Tcptp through substrate-trapping experiments and its hyperphosphorylation in Tcptp−/− macrophages. Tcptp−/− macrophages also have increased tyrosine phosphorylation and recruitment of a Grb2/Gab2/Shp2 complex to the CSF-1R and enhanced activation of Erk after CSF-1 stimulation, which are important molecular events in CSF-1-induced differentiation. These data implicate Tcptp as a critical regulator of CSF-1 signaling and mononuclear phagocyte development in hematopoiesis.

scholarly journals The T Cell Protein Tyrosine Phosphatase Is a Negative Regulator of Janus Family Kinases 1 and 3

2002 ◽  
Vol 12 (6) ◽  
pp. 446-453 ◽  
Author(s):  
Paul D. Simoncic ◽  
Ailsa Lee-Loy ◽  
Dwayne L. Barber ◽  
Michel L. Tremblay ◽  
C.Jane McGlade
Keyword(s):  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Cell Protein ◽  
Protein Tyrosine

scholarly journals Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

2019 ◽  
Author(s):  
M Wei ◽  
MG Haney ◽  
JS Blackburn
Keyword(s):  
Cell Migration ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Knock Down ◽  
Src Signaling ◽  
Cell Acute Lymphoblastic Leukemia

AbstractT-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive blood cancer, and currently, there are no immunotherapies or molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression is critical for development of new therapies for T-ALL. Here, we determined that Protein Tyrosine Phosphatase 4A3 (PTP4A3) plays a critical role in disease initiation and progression by promoting cell migration in T-ALL. PTP4A3 expression was upregulated in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Inhibition of PTP4A3 function with a small molecule inhibitor and knock-down of PTP4A3 expression using short-hairpin RNA (shRNA) in human T-ALL cells significantly impeded T-ALL cell migration capacityin vitroand reduced their ability to engraft and proliferatein vivoin xenograft mouse models. Additionally, PTP4A3 overexpression in aMyc-induced zebrafish T-ALL model significantly accelerated disease onset and shortened the time needed for cells to enter blood circulation. Reverse phase protein array (RPPA) revealed that manipulation of PTP4A3 expression levels in T-ALL cells directly affected the SRC signaling pathway, which plays a well-characterized role in migratory behavior of several cell types. Taken together, our study revealed that PTP4A3 is a key regulator of T-ALL migration via SRC signaling, and suggests that PTP4A3 plays an important role as an oncogenic driver in T-ALL.HighlightsA subset of T-cell Acute Lymphoblastic Leukemia (T-ALL) highly express the phosphatase PTP4A3PTP4A3 expression promotes leukemia development in zebrafish T-ALL modelsLoss of PTP4A3 prevents T-ALL engraftment in mouse xenograft modelsKnock-down or small molecule inhibition of PTP4A3 prevents T-ALL migration in part via modulation of SRC signaling.

scholarly journals Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2110-2120 ◽  
Author(s):  
Jihua Cheng ◽  
Andre R. Kydd ◽  
Koichi Nakase ◽  
Kristin M. Noonan ◽  
Akikazu Murakami ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Promoter Activity ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Protein Tyrosine ◽  
P2 Promoter

AbstractExpression of SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1), a candidate tumor suppressor, is repressed in human T-cell leukemia virus type-1 (HTLV-1)–transformed lymphocyte cell lines, adult T-cell leukemia (ATL) cells, and in other hematologic malignancies. However, the mechanisms underlying regulation and repression of SHP-1 remain unclear. Herein, we cloned the putative full-length, hematopoietic cell–specific SHP-1 P2 promoter and identified the “core” promoter regions. HTLV-1 Tax profoundly represses P2 promoter activity and histone deacetylase-1 (HDAC1) potentiates such inhibition. NF-κB was implicated as both a rate-limiting factor for basal P2 promoter activity and important for Tax-induced promoter silencing (TIPS). Chromatin immunoprecipitation studies demonstrated that NF-κB dissociates from the SHP-1 P2 promoter following the binding of Tax and HDAC1. This is in agreement with coimmunoprecipitation studies where NF-κB competed with HDAC1 for association with Tax protein. We propose that in TIPS, Tax recruits HDAC1 to the SHP-1 P2 promoter and forms an inhibitory complex that results in deacetylation and dissociation of NF-κB from the promoter and attenuation of SHP-1 expression. TIPS provides a possible first step toward HTLV-1 leukemogenesis through its down-modulation of this key immediate early negative regulator of IL-2 signaling.

scholarly journals Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia

2010 ◽  
Vol 42 (6) ◽  
pp. 530-535 ◽  
Author(s):  
Maria Kleppe ◽  
Idoya Lahortiga ◽  
Tiama El Chaar ◽  
Kim De Keersmaecker ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Cell Acute Lymphoblastic Leukemia

T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3457-3464 ◽  
Author(s):  
Krista M. Heinonen ◽  
Frederick P. Nestel ◽  
Evan W. Newell ◽  
Gabrielle Charette ◽  
Thomas A. Seemayer ◽  
...  
Keyword(s):  
T Cell ◽  
Inflammatory Disease ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Interferon Γ ◽  
Negative Regulator ◽  
Cell Protein ◽  
Protein Tyrosine ◽  
Systemic Inflammatory Disease

Abstract The deregulation of the immune response is a critical component in inflammatory disease. Recent in vitro data show that T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of cytokine signaling. Furthermore, tc-ptp-/- mice display immune defects and die within 5 weeks of birth. We report here that tc-ptp-/- mice develop progressive systemic inflammatory disease as shown by chronic myocarditis, gastritis, nephritis, and sialadenitis as well as elevated serum interferon-γ. The widespread mononuclear cellular infiltrates correlate with exaggerated interferon-γ, tumor necrosis factor-α, interleukin-12, and nitric oxide production in vivo. Macrophages grown from tc-ptp-/- mice are inherently hypersensitive to lipopolysaccharide, which can also be detected in vivo as an increased susceptibility to endotoxic shock. These results identify T-cell protein tyrosine phosphatase as a key modulator of inflammatory signals and macrophage function. (Blood. 2004;103:3457-3464)

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