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Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia

Leukemia volume 24, pages 239–242 (2010)Cite this article

We have recently shown that constitutive activation of PI3K/Akt signaling pathway is a very common event in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and is critical for leukemic cell viability. PI3K/Akt pathway hyperactivation appears to result mainly from post-translational inactivation of the phosphatase and tensin homolog (PTEN) protein, which is the main negative regulator of PI3K/Akt pathway.1 However, a relatively small but significant subset of newly diagnosed T-ALL patient samples are known to present inactivating PTEN gene mutations.1, 2, 3, 4, 5 PTEN mutation may collaborate with PTEN post-translational inactivation to maximize PTEN functional deficiency, thus contributing to increased PI3K/Akt activation and finally to leukemia resistance to chemotherapy. In fact, the occurrence of PTEN mutation/deletion is highly frequent in human T-ALL cell lines derived from relapsed patients. Moreover, PTEN mutation was reported to occur in 2 of 35 relapsed T-ALL as a secondary event during disease progression.3 As discussed below, the clinical relevance of PTEN mutations in pediatric T-ALL is available for only a limited number of patients4, 6 and should be analyzed with caution. Here, we report the prognostic impact of PTEN exon 7 mutations in a larger series of consecutive pediatric ALL patients treated in a single institution. Our results favor the notion that PTEN mutations can have a prognostic impact in pediatric T-ALL.

Bone marrow samples were obtained at diagnosis from 63 and 71 consecutive children (>1 month and <18, except for a 19- and 23-year-old T-ALL patients) with previously untreated T-ALL and precursor B-cell ALL, respectively. The group of T-ALL patients had a partial overlap with those we previously reported in the context of the post-translational inactivation of PTEN protein (18/63).1 Patients were registered at Boldrini Children's Center between 2000 and 2008, and were treated according to the Brazilian GBTLI ALL-99 Childhood Treatment protocol.7 Three T-ALL patients received corticosteroid before diagnosis but all had >50% blasts in diagnostic bone marrow aspirates and accordingly were included in the study. One patient had no DNA available (final n=62). Median follow-up was 4.4 years (interquartile range 2.4–6.8 years) for patients still alive and 1.4 years for those who died (interquartile range 0.3–1.8 years). The study was approved by the Research Ethics Committee from both Centro Infantil Boldrini and State University of Campinas.

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References

  1. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008; 118: 3762–3774.

    Article  CAS  Google Scholar 

  2. Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 2007; 447: 966–971.

    Article  CAS  Google Scholar 

  3. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203–1210.

    Article  CAS  Google Scholar 

  4. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647–650.

    Article  CAS  Google Scholar 

  5. Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A et al. High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-{beta} and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response. Blood 2009; 114: 1053–1062.

    Article  CAS  Google Scholar 

  6. Larson GA, Chen Q, Kugel DS, Ge Y, Lafiura K, Haska CL et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia 2009; 23: 1417–1425.

    Article  Google Scholar 

  7. Cortez MA, Scrideli CA, Yunes JA, Valera ET, Toledo S, Pavoni-Ferreira PCB et al. mRNA expression profile of multidrug resistance genes in childhood acute lymphoblastic leukemia. Low expression levels associated with a higher risk of toxic death. Pediatric Blood Câncer 2009; 53: 996–1004.

    Article  Google Scholar 

  8. Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H . The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci USA 1999; 96: 10182–10187.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 08/10034-1), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 401122/2005-0) and Fundação para a Ciência e a Tecnologia (POCI-PPCDT/SAU-OBS/58913 and PTDC/SAU-OBD/69974). PYJ, MAG and MBV have FAPESP, CAPES and CNPq scholarships, respectively. AS has FCT-SFRH PhD fellowships.

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Authors and Affiliations

  1. Centro Infantil Boldrini, Laboratório de Biologia Molecular, Campinas, Sao Paulo, Brazil

    P Y Jotta, M A Ganazza, L J G Zambaldi, S R Brandalise & J A Yunes

  2. Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University Medical School, Lisboa, Portugal

    A Silva & J T Barata

  3. Depto. de Pediatria, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    M B Viana

  4. Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Campinas, Sao Paulo, Brazil

    M J da Silva

  5. Depto. de Pediatria, Universidade Estadual de Campinas, Campinas, Sao Paulo, Brazil. E-mail: andres@boldrini.org.br,

    S R Brandalise

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  1. P Y Jotta
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Jotta, P., Ganazza, M., Silva, A. et al. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 24, 239–242 (2010). https://doi.org/10.1038/leu.2009.209

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