Overexpression of PTP4A3 in ETV6-RUNX1 acute lymphoblastic leukemia

Grönroos, Toni; Teppo, Susanna; Mehtonen, Juha; Laukkanen, Saara; Liuksiala, Thomas; Nykter, Matti; Heinäniemi, Merja; Lohi, Olli

doi:10.1016/j.leukres.2016.12.005

Cited by 4 publications

(5 citation statements)

References 23 publications

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“…Whether PRL-3, as a phosphatase, is directly involved in inhibition the transportation, the conversion to the active form, or another mechanism, needs to be further explored. For the other drugs, we did not observe any difference in viability, which is in accordance with others [ 19 ].…”

Section: Discussionsupporting

confidence: 93%

“…We detected PRL-3 in most of our B-ALL samples, and in the Oncomine datasets PRL-3 was significantly higher expressed in B-ALL cells compared to normal control cells. ETV6-RUNX1- and BCR-ABL1-positive cases had a higher PRL-3 expression compared to negative samples, as also shown by others [ 18 , 19 ]. Still, even translocation-negative samples expressed PRL-3 .…”

Section: Discussionsupporting

confidence: 80%

“…PRL-3 mRNA is highly expressed in BCR-ABL ALL [ 18 ], and was found overexpressed in ETV6-RUNX1 ALL, but did not impact cell viability [ 19 ]. Based on the oncogenic role and expression of PRL-3 in other hematological cancer, we aimed to explore PRL-3’s role in the pathogenesis of B-ALL.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatase of regenerating liver-3 is expressed in acute lymphoblastic leukemia and mediates leukemic cell adhesion, migration and drug resistance

et al. 2017

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Phosphatase of regenerating liver-3 (PRL-3/PTP4A3) is upregulated in multiple cancers, including BCR-ABL1- and ETV6-RUNX-positive acute lymphoblastic leukemia (ALL). With this study, we aim to characterize the biological role of PRL-3 in B cell ALL (B-ALL). Here, we demonstrate that PRL-3 expression at mRNA and protein level was higher in B-ALL cells than in normal cells, as measured by qRT-PCR or flow cytometry. Further, we demonstrate that inhibition of PRL-3 using shRNA or a small molecular inhibitor reduced cell migration towards an SDF-1α gradient in the preB-ALL cell lines Reh and MHH-CALL-4. Knockdown of PRL-3 also reduced cell adhesion towards fibronectin in Reh cells. Mechanistically, PRL-3 mediated SDF-1α stimulated calcium release, and activated focal adhesion kinase (FAK) and Src, important effectors of migration and adhesion. Finally, PRL-3 expression made Reh cells more resistance to cytarabine treatment. In conclusion, the expression level of PRL-3 was higher in B-ALL cells than in normal cells. PRL-3 promoted adhesion, migration and resistance to cytarabine. PRL-3 may represent a novel target in the treatment of B-ALL.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

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Phosphatase of regenerating liver-3 is expressed in acute lymphoblastic leukemia and mediates leukemic cell adhesion, migration and drug resistance

et al. 2017

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“…This may lead to near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Furthermore, two recent studies showed a novel cooperative activity of E/R with the antiapoptotic protein BCL2 [94] and the protein tyrosine phosphatase 4A3 (PTP4A3) [95], although the impact on leukemia progression needs to be further explored.…”

Section: Pathogenesis Of Etv6/runx1-positive Childhood Allmentioning

confidence: 99%

Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

2017

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ETV6/RUNX1 (E/R) is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL). Multiple lines of evidence imply a “two-hit” model for the molecular pathogenesis of E/R-positive ALL, whereby E/R rearrangement is followed by a series of secondary mutations that trigger overt leukemia. The cellular framework in which E/R arises and the maintenance of a pre-leukemic condition by E/R are fundamental to the mechanism that underlies leukemogenesis. Accordingly, a variety of studies have focused on the relationship between the clones giving rise to the primary and recurrent E/R-positive ALL. We review here the most recent insights into the pathogenic mechanisms underlying E/R-positive ALL, as well as the molecular abnormalities prevailing at relapse.

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“…PTP4A3 participates in many cellular processes, such as proliferation, survival, motility and invasion (34,35). PTP4A3 expression has been documented as being significantly elevated in a variety of solid tumor types compared with healthy tissues, as well as in acute myeloid leukemia (AML) and ALL cells (36,37). In this study, we observed the level of PTP4A3 to be reduced in MOLT-4 cells treated with the combination of both drugs.…”

Section: Discussionmentioning

confidence: 56%

Combination of ERK2 and STAT3 Inhibitors Promotes Anticancer Effects on Acute Lymphoblastic Leukemia Cells

Jasek-Gajda

Jurkowska

Jasińska

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Deregulated activation of signaling through the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ ERK) and signal transducer and activator of transcription (STAT) pathways is involved in numerous hematological malignancies, making it an attractive therapeutic target. This study aimed to assess the effect of the combination of ERK2 inhibitor VX-11e and STAT3 inhibitor STA-21 on acute lymphoblastic leukemia cell lines REH and MOLT-4. Materials and Methods: REH and MOLT-4 cell lines were cultured with each drug alone and in combination. Cell viability, ERK activity, cell cycle distribution, apoptosis and oxidative stress induction were assessed by flow cytometry. Protein levels of STAT3, phospho-STAT3, protein tyrosine phosphatase 4A3 (PTP4A3), survivin, p53 and p21 were determined by western blotting. Results: VX-11e in combination with STA-21 significantly inhibited cell viability, induced G 0 /G 1 cell-cycle arrest, enhanced production of reactive oxygen species, and induced apoptosis. These effects were associated with an increased level of p21 protein in REH cells and with reduced levels of phopho-STAT3, survivin and PTP4A3 proteins in MOLT-4 cells. Conclusion: Our findings provide a rationale for combined inhibition of RAS/RAF/MEK/ERK and STAT3 pathways in order to enhance anticancer effects against acute lymphoblastic leukemia cells.

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Overexpression of PTP4A3 in ETV6-RUNX1 acute lymphoblastic leukemia

Cited by 4 publications

References 23 publications

Phosphatase of regenerating liver-3 is expressed in acute lymphoblastic leukemia and mediates leukemic cell adhesion, migration and drug resistance

Phosphatase of regenerating liver-3 is expressed in acute lymphoblastic leukemia and mediates leukemic cell adhesion, migration and drug resistance

Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

Combination of ERK2 and STAT3 Inhibitors Promotes Anticancer Effects on Acute Lymphoblastic Leukemia Cells

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