- Short communication
- Open Access
The pro-metastasis tyrosine phosphatase, PRL-3 (PTP4A3), is a novel mediator of oncogenic function of BCR-ABL in human chronic myeloid leukemia
© Zhou et al.; licensee BioMed Central Ltd. 2012
- Received: 2 July 2012
- Accepted: 14 September 2012
- Published: 21 September 2012
Resistance to tyrosine kinase inhibitors (TKIs) remains a challenge in management of patients with chronic myeloid leukemia (CML). A better understanding of the BCR-ABL signalling network may lead to better therapy.
Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 (PTP4A3), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BCR-ABL reduces PRL-3 and increases cleavage of PARP. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing P210 T315I. Finally, analysis with specific shRNA shows PRL-3 involvement in the proliferation and self-renewal of CML cells.
These data support a role for PRL-3 in BCR-ABL signalling and CML biology and may be a potential therapeutic target downstream of BCR-ABL in TKI resistant mutant cells.
- Chronic myeloid leukemia (CML)
- Protein-tyrosine phosphatase of regenerating liver 3 (PRL-3)
- Tyrosine kinase inhibitor (TKI)
Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy with a hallmark cytogenetic abnormality, i.e., the BCR-ABL fusion oncogene, resulting from the reciprocal translocation of chromosomes 9 and 22 [also known as Philadelphia (Ph) chromosome]. CML is the best and most successful disease model for tyrosine kinase inhibitor (TKI) therapy[2, 3]. Unfortunately, acquired resistance can develop during the course of treatment. Effective therapies that can overcome resistance still remain a challenge for the clinical management of CML[2, 4]. The mechanism of BCR-ABL induced transformation and signaling transduction networks have been intensively characterized over the decades[5–7]. However, new discoveries related to the BCR-ABL signaling pathway and mechanisms of TKI resistance continues to emerge, leading to a better understanding of disease progression and development of novel therapy[8–10].
Protein-tyrosine phosphatase of regenerating liver 3 (PRL-3, encoded by protein tyrosine phosphatase type IVA 3, PTP4A3) belongs to class I cysteine-based protein tyrosine phosphatases (PTPs) with dual-specificity[11–13]. PRL-3 has been identified as a critical player in cancer cell metastasis, invasion, migration, and tumor angiogenesis[11, 14–16]. The association between elevated PRL-3 and the development of various human cancers has been validated in a wide range of solid tumors[11, 14, 15] and multiple myeloma.
We recently discovered that poly(rC) binding protein 1 (PCPB1, also known as heterogenous nuclear ribonucleoprotein E1, hnRNP-E1) inhibited PRL-3 protein through binding 5’-UTR (untranslated region) of PRL-3 mRNA and showed that PRL-3, acting as a downstream target of the internal tandem duplication (ITD) of fms-like tyrosine kinase (FLT3) signaling, was implicated in FLT3 inhibitor therapy in acute myeloid leukemia (AML). Furthermore, PRL-3 also has been demonstrated as an independent prognostic parameter for poor overall survival (OS) and event-free survival (EFS) in AML. Importantly, targeting intracellular PRL-3 protein suppressed cancer growth. In the present study, we hypothesize that PRL-3 might be involved in leukemogenesis of human CML.
In summary, the present study demonstrates that PRL-3 is upregulated in human CML cell lines, BCR-ABL transformed cell lines and primary CML patient samples. Interestingly, in a previous study, high expression of PRL-3 has been associated with aggressive phenotype of BCR-ABL positive acute lymphoblastic leukemia (ALL). This finding, together with our results highlight that PRL-3 is a novel downstream target of the BCR-ABL signalling pathway, and may be a novel mediator of BCR-ABL oncogenic functions such as cell survival and self-renewal. Suppression of PRL-3 could provide potential opportunity for further improving anti-CML therapy, especially in tumors with Imatinib or TKI resistant BCR-ABL mutants.
The authors thank Dr. Charles Chuah (Duke-NUS Graduate Medical School, Singapore) for his critical suggestions and Dr. Brian Druker (Oregon Health & Science University, USA) for providing P210 WT, P210 T315I, P210 M351T, P210 H396R cells. We are grateful to Drs. Akira Kawasaki and Akihiko Numata (Cancer Science Institute of Singapore, NUS) for sharing KCL-22. We are in debt of Prof Sir David Lane (A*Star, Singapore) for providing novel reagents and suggestions. We thank Dr. Shing-Leng Chan (Cancer Science Institute of Singapore) for providing NOD/SCID mice.
This work was supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program to W-J.C. W-J.C. is also supported by NMRC Clinician Scientist Investigator award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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