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 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

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 Phloridzin Docosahexaenoate (PZ-DHA) : A Novel Naturally Derived Drug Active in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5197-5197
Author(s):  
Niroshaathevi Arumuggam ◽  
Nicole Melong ◽  
Catherine K.L. Too ◽  
Jason N. Berman ◽  
H.P. Vasantha Rupasinghe
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Xenograft Model ◽  
Jurkat Cells ◽  
Interferon Α ◽  
Omega 3 ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant disease that accounts for about 15% of pediatric and 25% of adult ALL. Although risk stratification has provided more tailored therapy and improved the overall survival of T-ALL patients, clinical challenges such as suboptimal drug responses, morbidity from drug toxicities, and drug resistance still exist. Plant polyphenols have therapeutic efficacy as pharmacological adjuvants to help overcome these challenges. They can be acylated with fatty acids to overcome issues concerning bioavailability, such as poor intestinal absorption and low metabolic stability. Phloridzin (PZ), a flavonoid found in apple peels, was acylated with an omega-3 fatty acid, docosahexaenoic acid (DHA), to generate a novel ester called phloridzin docosahexaenoate (PZ-DHA). The cytotoxic effect of PZ-DHA was studied in the human Jurkat T-ALL cell line. PZ-DHA significantly reduced the viability and cellular ATP levels of treated cells. PZ-DHA was found to selectively induce apoptosis in Jurkat cells, while sparing normal murine T-cells. Apoptosis was further confirmed by demonstrating the ability of PZ-DHA to induce morphological alterations, DNA fragmentation, caspase activation, and the release of intracellular lactate dehydrogenase. PZ-DHA also significantly inhibited cell division in Jurkat cells. Furthermore, interferon-α-induced phosphorylation of the transcription factor, STAT3, was downregulated following PZ-DHA treatment. The in vitro efficacy of PZ-DHA was recapitulated in vivo in an established zebrafish xenograft model, where the proliferation of transplanted Jurkat cells was inhibited when PZ-DHA was added to the embryo water. Overall, these findings provide evidence for PZ-DHA as a novel therapeutic agent with activity in T-ALL. Studies examining the effect of PZ-DHA on patient-derived ALL cells engrafted in zebrafish are currently underway. Disclosures No relevant conflicts of interest to declare.

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.

Essential Role for Mir-181a1/b1 In T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 470-470
Author(s):  
Ana Rita Fragoso ◽  
Tin Mao ◽  
Song Wang ◽  
Steven Schaffert ◽  
Hyeyoung Min ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Essential Role ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Cancer Development ◽  
Loss Of Function ◽  
Control Of Gene Expression ◽  
Mirna Genes ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 470 MiRNA-mediated gene regulation represents a fundamental layer of post-transcriptional control of gene expression with diverse functional roles in normal development and tumorigenesis. Whereas some studies have shown that over-expression of miRNA genes may contribute to cancer development and progression, it is yet to be rigorously tested by the loss-of-function genetic approaches whether miRNA genes are required for cancer development and maintenance in mice. Here we show that mir-181a1/b1 coordinates Notch and pre-TCR signals during normal thymocyte differentiation and plays an essential role in development and onset of T-cell acute lymphoblastic leukemia (T-ALL) induced by some Notch mutations. Using gain-of-function and loss-of-function approaches, we demonstrated that mir-181a1/b1 controls Notch and pre-TCR receptor signals during the early stages of T cell development in the thymus by repressing multiple negative regulators of both pathways, including Nrarp, PTPN-22, SHP2, DUSP5, and DUSP6. These results illustrate that a single miRNA can coordinate multiple signaling pathways by modulating the timing and strength of signaling at different stages. Intriguingly, synergistic signaling between Notch and pre-TCR pathways is necessary for the development of T-ALL, and miR-181 family miRNAs are aberrantly expressed in T-ALL patients. These observations raise the possibility that mir-181a1/b1 might contribute to the onset or maintenance of T-ALL by targeting similar pathways in tumor cells as it does in normal thymic progenitor cells. In support of this notion, we found that loss of mir-181a1/b1 significantly delayed the onset and development of T-ALL induced by intracellular domain of Notch1 (ICN1) and caused a 32% increase in the median survival time from 41 days to 54 days in T-ALL mice. Importantly, we noted that loss of mir-181a1/b1 more efficiently repressed the leukemogeneic potential of cells with lower levels of ICN1 expression, suggesting that mir-181a1/b1 may be more effective in inhibiting T-ALL development induced by a Notch mutant with weaker signal strength. Indeed, we demonstrated that loss of mir-181a1b1 essentially blocked T-ALL development induced by the weaker Notch mutant and dramatically decreased mortality from 60% to 10% in these T-ALL mice. Since human Notch mutations identified in T-ALL patients generally have weaker signaling strength and lower oncogenic potential than that of ICN1, our findings indicate that mir-181a1/b1 may play an essential role in development of normal thymic progenitors and Notch-induced T-ALL and may be targeted to treat T-ALL patients harboring Notch mutations. Disclosures: No relevant conflicts of interest to declare.

Transcriptional Repression of the LMO2 Oncogene By Ikaros in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 439-439
Author(s):  
Yali Ding ◽  
Chunhua Song ◽  
Chandrika S. Gowda ◽  
Malika Kapadia ◽  
Kimberly Payne ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Chromatin Immunoprecipitation ◽  
Transcriptional Repression ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Transcriptional Level ◽  
Knock Down ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Ck2 Inhibitors

Abstract LIM domain only protein 2 (LMO2) is a regulator of hematopoiesis and an oncogene that is overexpressed in a subset of T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of LMO2 in T-ALL is associated with a poor prognosis. The mechanisms that regulate LMO2 expression in T-ALL are still unknown. Here, we present evidence that expression of LMO2 in T-ALL is regulated at the transcriptional level by Ikaros, a tumor suppressor protein whose deletion is associated with the development T-ALL. Global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) studies in primary human acute lymphoblastic leukemia cells and in cell lines demonstrated Ikaros occupancy of the LMO2 promoter. Ikaros binding at the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary T-ALL and B-ALL cells. The role of Ikaros in the regulation of LMO2 transcription in T-ALL was tested using gain-of-function and loss-of-function experiments. Ikaros knock-down with siRNA resulted in increased transcription of LMO2 in T-ALL. Overexpression of Ikaros in human T-ALL was associated with strongly reduced transcription of LMO2. In mice, T-ALL cells that are derived from Ikaros-knockout mice express high levels of LMO2. Transduction of these cells with Ikaros-containing retrovirus, results in a sharp reduction of LMO2 expression. Since Ikaros function in T-ALL is negatively regulated by the pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition can enhance Ikaros-mediated transcriptional repression of LMO2. Molecular inhibition of CK2 using shRNA, as well as pharmacological inhibition with a specific CK2 inhibitor, resulted in reduced expression of LMO2 in primary human T-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the LMO2 promoter. Ikaros knock-down restored high expression of LMO2 in T-ALL cells that were treated with CK2 inhibitors. These data show that Ikaros is a major regulator of LMO2 transcription in T-ALL and that CK2 inhibition requires Ikaros activity to repress LMO2 transcription. Increased Ikaros binding was associated with reduced histone H3K9ac and H3K4me3 marks at the LMO2 promoter suggesting that Ikaros regulates LMO2 transcription via chromatin remodeling. In conclusion, these results provide evidence that expression of the LMO2 oncogene is regulated by Ikaros and CK2 in T-ALL. Targeting CK2 with specific inhibitors has been used as a therapeutic strategy in a preclinical model of T-ALL. The presented data reveal a novel mechanism of therapeutic action for CK2 inhibitors - repression of LMO2 expression via Ikaros. These results provide a rationale for the use of CK2 inhibitors in T-ALL with LMO2 overexpression. Disclosures No relevant conflicts of interest to declare.

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