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) 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.
Overexprsesion of PRL-3 in CML cell lines and primary patient samples
Imatinib suppressed PRL-3 through inhibition of STAT pathway
Silencing BCR-ABL fusion gene or STAT3 decreased PRL-3 expression
PRL-3 is involved in CML proliferation, self-renewal, tumorigenic capacity and drug response
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.
- Van Etten RA: Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res. 2004, 28 (Suppl 1): S21-S28.View ArticlePubMedGoogle Scholar
- Druker BJ: Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008, 112: 4808-4817. 10.1182/blood-2008-07-077958View ArticlePubMedGoogle Scholar
- Radich JP: Chronic myeloid leukemia 2010: where are we now and where can we go?. Hematology Am Soc Hematol Educ Program. 2010, 2010: 122-128. 10.1182/asheducation-2010.1.122View ArticlePubMedGoogle Scholar
- Hochhaus A: First-Line management of CML: a state of the art review. J Natl Compr Canc Netw. 2008, 6 (Suppl 2): S1-S10.PubMedGoogle Scholar
- Druker BJ, Sawyers CL, Capdeville R, Ford JM, Baccarani M, Goldman JM: Chronic myelogenous leukemia. Hematology (Am Soc Hematol Educ Program). 2001: 87-112.Google Scholar
- Hantschel O, Superti-Furga G: Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004, 5: 33-44. 10.1038/nrm1280View ArticlePubMedGoogle Scholar
- Sattler M, Griffin JD: Molecular mechanisms of transformation by the BCR-ABL oncogene. Semin Hematol. 2003, 40: 4-10.View ArticlePubMedGoogle Scholar
- La Rosee P, Deininger MW: Resistance to imatinib: mutations and beyond. Semin Hematol. 2010, 47: 335-343. 10.1053/j.seminhematol.2010.06.005View ArticlePubMedGoogle Scholar
- Melo JV, Chuah C: Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematology Am Soc Hematol Educ Program. 2008: 427-435.Google Scholar
- Roumiantsev S, Shah NP, Gorre ME, Nicoll J, Brasher BB, Sawyers CL, Van Etten RA: Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci U S A. 2002, 99: 10700-10705. 10.1073/pnas.162140299PubMed CentralView ArticlePubMedGoogle Scholar
- Bessette DC, Wong PC, Pallen CJ: PRL-3: a metastasis-associated phosphatase in search of a function. Cells Tissues Organs. 2007, 185: 232-236. 10.1159/000101324View ArticlePubMedGoogle Scholar
- Basak S, Jacobs SB, Krieg AJ, Pathak N, Zeng Q, Kaldis P, Giaccia AJ, Attardi LD: The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Mol Cell. 2008, 30: 303-314. 10.1016/j.molcel.2008.04.002PubMed CentralView ArticlePubMedGoogle Scholar
- Winter-Vann AM, Casey PJ: Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer. 2005, 5: 405-412. 10.1038/nrc1612View ArticlePubMedGoogle Scholar
- Al-Aidaroos AQ, Zeng Q: PRL-3 phosphatase and cancer metastasis. J Cell Biochem. 2010, 111: 1087-1098. 10.1002/jcb.22913View ArticlePubMedGoogle Scholar
- Stephens BJ, Han H, Gokhale V, Von Hoff DD: PRL phosphatases as potential molecular targets in cancer. Mol Cancer Ther. 2005, 4: 1653-1661. 10.1158/1535-7163.MCT-05-0248View ArticlePubMedGoogle Scholar
- Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, St Croix B, Romans KE, Choti MA, Lengauer C, Kinzler KW, Vogelstein B: A phosphatase associated with metastasis of colorectal cancer. Science. 2001, 294: 1343-1346. 10.1126/science.1065817View ArticlePubMedGoogle Scholar
- Fagerli UM, Holt RU, Holien T, Vaatsveen TK, Zhan F, Egeberg KW, Barlogie B, Waage A, Aarset H, Dai HY: Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood. 2008, 111: 806-815. 10.1182/blood-2007-07-101139PubMed CentralView ArticlePubMedGoogle Scholar
- Wang H, Vardy LA, Tan CP, Loo JM, Guo K, Li J, Lim SG, Zhou J, Chng WJ, Ng SB: PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer Cell. 2010, 18: 52-62. 10.1016/j.ccr.2010.04.028View ArticlePubMedGoogle Scholar
- Zhou J, Bi C, Chng WJ, Cheong LL, Liu SC, Mahara S, Tay KG, Zeng Q, Li J, Guo K: PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy. PLoS One. 2011, 6: e19798- 10.1371/journal.pone.0019798PubMed CentralView ArticlePubMedGoogle Scholar
- Beekman R, Valkhof M, Erkeland SJ, Taskesen E, Rockova V, Peeters JK, Valk PJ, Lowenberg B, Touw IP: Retroviral Integration Mutagenesis in Mice and Comparative Analysis in Human AML Identify Reduced PTP4A3 Expression as a Prognostic Indicator. PLoS One. 2011, 6: e26537- 10.1371/journal.pone.0026537PubMed CentralView ArticlePubMedGoogle Scholar
- Guo K, Li J, Tang JP, Tan CP, Hong CW, Al-Aidaroos AQ, Varghese L, Huang C, Zeng Q: Targeting intracellular oncoproteins with antibody therapy or vaccination. Sci Transl Med. 2011, 3: 99ra85- 10.1126/scitranslmed.3002296PubMedGoogle Scholar
- Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005, 353: 172-187. 10.1056/NEJMra044389View ArticlePubMedGoogle Scholar
- Hehlmann R, Hochhaus A, Baccarani M: Chronic myeloid leukaemia. Lancet. 2007, 370: 342-350. 10.1016/S0140-6736(07)61165-9View ArticlePubMedGoogle Scholar
- Scherr M, Battmer K, Winkler T, Heidenreich O, Ganser A, Eder M: Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood. 2003, 101: 1566-1569. 10.1182/blood-2002-06-1685View ArticlePubMedGoogle Scholar
- Juric D, Lacayo NJ, Ramsey MC, Racevskis J, Wiernik PH, Rowe JM, Goldstone AH, O’Dwyer PJ, Paietta E, Sikic BI: Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias. J Clin Oncol. 2007, 25: 1341-1349. 10.1200/JCO.2006.09.3534View ArticlePubMedGoogle Scholar
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