Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Original Articles

NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols

Leukemia volume 24, pages 2014–2022 (2010)Cite this article

Subjects

Abstract

Aberrant activation of the NOTCH1 pathway by inactivating and activating mutations in NOTCH1 or FBXW7 is a frequent phenomenon in T-cell acute lymphoblastic leukemia (T-ALL). We retrospectively investigated the relevance of NOTCH1/FBXW7 mutations for pediatric T-ALL patients enrolled on Dutch Childhood Oncology Group (DCOG) ALL7/8 or ALL9 or the German Co-Operative Study Group for Childhood Acute Lymphoblastic Leukemia study (COALL-97) protocols. NOTCH1-activating mutations were identified in 63% of patients. NOTCH1 mutations affected the heterodimerization, the juxtamembrane and/or the PEST domains, but not the RBP-J-κ-associated module, the ankyrin repeats or the transactivation domain. Reverse-phase protein microarray data confirmed that NOTCH1 and FBXW7 mutations resulted in increased intracellular NOTCH1 levels in primary T-ALL biopsies. Based on microarray expression analysis, NOTCH1/FBXW7 mutations were associated with activation of NOTCH1 direct target genes including HES1, DTX1, NOTCH3, PTCRA but not cMYC. NOTCH1/FBXW7 mutations were associated with TLX3 rearrangements, but were less frequently identified in TAL1- or LMO2-rearranged cases. NOTCH1-activating mutations were less frequently associated with mature T-cell developmental stage. Mutations were associated with a good initial in vivo prednisone response, but were not associated with a superior outcome in the DCOG and COALL cohorts. Comparing our data with other studies, we conclude that the prognostic significance for NOTCH1/FBXW7 mutations is not consistent and may depend on the treatment protocol given.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Pieters R, Carroll WL . Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin North Am 2008; 55: 1–20, ix.

    Article  Google Scholar 

  2. Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.

    Article  CAS  Google Scholar 

  3. Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A et al. Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood 2004; 103: 442–450.

    Article  CAS  Google Scholar 

  4. Meijerink JP, den Boer ML, Pieters R . New genetic abnormalities and treatment response in acute lymphoblastic leukemia. Semin Hematol 2009; 46: 16–23.

    Article  Google Scholar 

  5. Van Vlierberghe P, Pieters R, Beverloo HB, Meijerink JP . Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol 2008; 143: 153–168.

    Article  CAS  Google Scholar 

  6. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66: 649–661.

    Article  CAS  Google Scholar 

  7. Suzuki S, Nagel S, Schneider B, Chen S, Kaufmann M, Uozumi K et al. A second NOTCH1 chromosome rearrangement: t(9;14)(q34.3;q11.2) in T-cell neoplasia. Leukemia 2009; 23: 1003–1006.

    Article  CAS  Google Scholar 

  8. Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.

    Article  CAS  Google Scholar 

  9. Sulis ML, Williams O, Palomero T, Tosello V, Pallikuppam S, Real PJ et al. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 2008; 112: 733–740.

    Article  CAS  Google Scholar 

  10. Grabher C, von Boehmer H, Look AT . Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6: 347–359.

    Article  CAS  Google Scholar 

  11. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 2006; 103: 18261–18266.

    Article  CAS  Google Scholar 

  12. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20: 2096–2109.

    Article  CAS  Google Scholar 

  13. Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Corcoran M, Heyman M et al. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res 2007; 67: 5611–5616.

    Article  CAS  Google Scholar 

  14. O’Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 2007; 204: 1813–1824.

    Article  Google Scholar 

  15. Park MJ, Taki T, Oda M, Watanabe T, Yumura-Yagi K, Kobayashi R et al. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol 2009; 145: 198–206.

    Article  CAS  Google Scholar 

  16. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 2007; 204: 1825–1835.

    Article  CAS  Google Scholar 

  17. Breit S, Stanulla M, Flohr T, Schrappe M, Ludwig WD, Tolle G et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006; 108: 1151–1157.

    Article  CAS  Google Scholar 

  18. Zhu YM, Zhao WL, Fu JF, Shi JY, Pan Q, Hu J et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res 2006; 12: 3043–3049.

    Article  CAS  Google Scholar 

  19. van Grotel M, Meijerink JP, van Wering ER, Langerak AW, Beverloo HB, Buijs-Gladdines JG et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 2008; 22: 124–131.

    Article  CAS  Google Scholar 

  20. Larson Gedman A, Chen Q, Kugel Desmoulin S, 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  CAS  Google Scholar 

  21. Kamps WA, Bokkerink JP, Hahlen K, Hermans J, Riehm H, Gadner H et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988–1991). Blood 1999; 94: 1226–1236.

    CAS  Google Scholar 

  22. Kamps WA, Bokkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER et al. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996). Leukemia 2002; 16: 1099–1111.

    Article  CAS  Google Scholar 

  23. Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bokkerink JP, Bruin MC et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol 2009; 10: 957–966.

    Article  CAS  Google Scholar 

  24. van Grotel M, Meijerink JP, Beverloo HB, Langerak AW, Buys-Gladdines JG, Schneider P et al. The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols. Haematologica 2006; 91: 1212–1221.

    Google Scholar 

  25. Stam RW, den Boer ML, Meijerink JP, Ebus ME, Peters GJ, Noordhuis P et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood 2003; 101: 1270–1276.

    Article  CAS  Google Scholar 

  26. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.

    CAS  Google Scholar 

  27. Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J et al. The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood 2006; 108: 3520–3529.

    Article  CAS  Google Scholar 

  28. Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ et al. The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 2008; 111: 4668–4680.

    Article  CAS  Google Scholar 

  29. Hochberg Y, Benjamini Y . More powerful procedures for multiple significance testing. Stat Med 1990; 9: 811–818.

    Article  CAS  Google Scholar 

  30. Li C, Wong WH . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 2001; 98: 31–36.

    Article  CAS  Google Scholar 

  31. Paweletz CP, Charboneau L, Bichsel VE, Simone NL, Chen T, Gillespie JW et al. Reverse-phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 2001; 20: 1981–1989.

    Article  CAS  Google Scholar 

  32. Petricoin 3rd EF, Espina V, Araujo RP, Midura B, Yeung C, Wan X et al. Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res 2007; 67: 3431–3440.

    Article  CAS  Google Scholar 

  33. Lee JW, Soung YH, Kim HJ, Park WS, Nam SW, Kim SH et al. Mutational analysis of the hCDC4 gene in gastric carcinomas. Eur J Cancer 2006; 42: 2369–2373.

    Article  CAS  Google Scholar 

  34. Homminga I, langerak AW, De Laat W, de Rooij JJ, Stubbs A, Buijs-Gladdines J et al. NKX2-1 and MEF2C oncogenes delineate novel subtypes in T-cell acute lymphoblastic leukemia. (in preparation).

  35. Chiang MY, Xu L, Shestova O, Histen G, L′Heureux S, Romany C et al. Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest 2008; 118: 3181–3194.

    Article  CAS  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol 2009; 27: 4352–4356.

    Article  CAS  Google Scholar 

  38. Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR, Aster JC et al. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood 2009; 113: 4381–4390.

    Article  CAS  Google Scholar 

  39. Asnafi V, Radford-Weiss I, Dastugue N, Bayle C, Leboeuf D, Charrin C et al. CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage. Blood 2003; 102: 1000–1006.

    Article  CAS  Google Scholar 

  40. Eguchi-Ishimae M, Eguchi M, Kempski H, Greaves M . NOTCH1 mutation can be an early, prenatal genetic event in T-ALL. Blood 2008; 111: 376–378.

    Article  CAS  Google Scholar 

  41. Mansour MR, Duke V, Foroni L, Patel B, Allen CG, Ancliff PJ et al. Notch-1 mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia. Clin Cancer Res 2007; 13: 6964–6969.

    Article  CAS  Google Scholar 

  42. Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G et al. Prognostic significance of NOTCH1 and FBXW7 mutations in childhood T-cell acute leukemia: results from the EORTC Children Leukemia Group. Leukemia 2010, (this issue).

  43. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009; 15: 50–58.

    Article  CAS  Google Scholar 

  44. Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD et al. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL can be seperated from NOTCH pathway activation by FBXW7 loss of function. Leukemia 2010, (this issue).

  45. Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica 2009; 94: 1383–1390.

    Article  CAS  Google Scholar 

  46. Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 2009; 459: 1000–1004.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

LZ and WKS were financed by the Stichting Kinderen Kankervrij (KiKa; Grant no. KiKa 2007-012). IH was financed by the Dutch Cancer Society Dutch Cancer Society (KWF-EMCR 2006-3500) CK was financed by KiKa (Grant no. KiKa 2008-029). We thank the German Jose Carreras Leukemia Foundation (Grant no. SP 04/03 to MH).

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands

    L Zuurbier, I Homminga, ML te Winkel, J G C A M Buijs-Gladdines, C Kooi, W K Smits, R Pieters & J P P Meijerink

  2. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    V Calvert & E F Petricoin III

  3. The Dutch Childhood Oncology Group, The Hague, The Netherlands

    E Sonneveld, A J P Veerman & W A Kamps

  4. Department of Pediatric Oncology, Beatrix Children's Hospital, University of Groningen, Groningen, The Netherlands

    W A Kamps

  5. The German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany

    M Horstmann

  6. Clinic of Pediatric Hematology and Oncology, The Research Institute Children's Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    M Horstmann

  7. NCI–FDA Clinical Proteomics Program, Food and Drug Administration, Bethesda, MD, USA

    E F Petricoin III

Authors
  1. L Zuurbier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Homminga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Calvert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. ML te Winkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J G C A M Buijs-Gladdines
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Kooi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W K Smits
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Sonneveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A J P Veerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. W A Kamps
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Horstmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E F Petricoin III
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. R Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J P P Meijerink
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J P P Meijerink.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author contributions

LZ designed experiments, performed research and wrote the article; IH performed research and wrote the article; VC performed RPMA analysis; MLW performed research; JB-G performed NOTCH1 and FBXW7 mutation analysis; CK performed western blot analysis; WS prepared samples for RPMA analysis; ES, AJPV, WK and MH provided patient samples and clinical and immunophenotypic data; EP supervised study and wrote the article; RP designed and supervised study and wrote the article; JPPM was principal investigator, designed and supervised the study and wrote the article.

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuurbier, L., Homminga, I., Calvert, V. et al. NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia 24, 2014–2022 (2010). https://doi.org/10.1038/leu.2010.204

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.204

Keywords

This article is cited by

Search

Advanced search

Quick links