Acute lymphoblastic leukemia

Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia

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The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

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  1. 1

    Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

  2. 2

    Ciofani M, Zuniga-Pflucker JC . Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005; 6: 881–888.

  3. 3

    Juntilla MM, Koretzky GA . Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol Lett 2008; 116: 104–110.

  4. 4

    Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica 2013; 98: 928–936.

  5. 5

    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.

  6. 6

    Jenkinson S, Kirkwood AA, Goulden N, Vora A, Linch DC, Gale RE . Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial. Leukemia 2015; 30: 39–47.

  7. 7

    Jotta PY, Ganazza MA, Silva A, Viana MB, da Silva MJ, Zambaldi LJ et al. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 2010; 24: 239–242.

  8. 8

    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.

  9. 9

    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.

  10. 10

    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.

  11. 11

    Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 2013; 31: 4333–4342.

  12. 12

    Zuurbier L, Petricoin EF, Vuerhard MJ, Calvert V, Kooi C, Buijs-Gladdines J et al. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica 2012; 97: 1405–1413.

  13. 13

    Mendes RD, Sarmento LM, Cante-Barrett K, Zuurbier L, Buijs-Gladdines JG, Povoa V et al. PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 2014; 124: 567–578.

  14. 14

    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.

  15. 15

    Tesio M, Trinquand A, Macintyre E, Asnafi V . Oncogenic PTEN functions and models in T-cell malignancies. Oncogene 2015; 35: 3887–3896.

  16. 16

    Asnafi V, Buzyn A, Le Noir S, Baleydier F, Simon A, Beldjord K et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 2009; 113: 3918–3924.

  17. 17

    Bergeron J, Clappier E, Radford I, Buzyn A, Millien C, Soler G et al. Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood 2007; 110: 2324–2330.

  18. 18

    Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010; 26: 589–595.

  19. 19

    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010; 20: 1297–1303.

  20. 20

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al. The Sequence Alignment/Map format and SAM tools. Bioinformatics 2009; 25: 2078–2079.

  21. 21

    Martincorena I, Campbell PJ . Somatic mutation in cancer and normal cells. Science 2015; 349: 1483–1489.

  22. 22

    Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 2014; 157: 595–610.

  23. 23

    Gianfelici V, Chiaretti S, Demeyer S, Di Giacomo F, Messina M, La Starza R et al. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications. Haematologica 2016; 101: 941–950.

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AT was supported by a grant from INCa (Institut National du Cancer: «Soutien à la Recherche Translationnelle 2012»). MT was supported by Grants from Fondation de France (FdF) and Fondation pour la recherche sur le Cancer (ARC). This work was supported by grants from the ‘La Ligue Contre le Cancer’ and the ‘Association Laurette Fugain’.

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Correspondence to V Asnafi.

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