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NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia

Leukemia volume 23, pages 1374–1377 (2009)Cite this article

Abstract

Inhibition of NOTCH1 signaling with γ-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.

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References

  1. Ferrando AA, Look AT . Clinical implications of recurring chromosomal and associated molecular abnormalities in acute lymphoblastic leukemia. Semin Hematol 2000; 37: 381–395.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Chessells JM, Bailey C, Richards SM . Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia. Lancet 1995; 345: 143–148.

    Article  CAS  PubMed  Google Scholar 

  4. Pui CH, Evans WE . Acute lymphoblastic leukemia. N Engl J Med 1998; 339: 605–615.

    Article  CAS  PubMed  Google Scholar 

  5. Rivera GK, Raimondi SC, Hancock ML, Behm FG, Pui CH, Abromowitch M et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 1991; 337: 61–66.

    Article  CAS  PubMed  Google Scholar 

  6. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310–3322.

    CAS  PubMed  Google Scholar 

  7. Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97: 1211–1218.

    Article  CAS  PubMed  Google Scholar 

  8. Nachman JB, Heerema NA, Sather H, Camitta B, Forestier E, Harrison CJ et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood 2007; 110: 1112–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007; 109: 944–950.

    Article  CAS  PubMed  Google Scholar 

  10. Cornelissen JJ, van der Holt B, Verhoef GE, van’t Veer MB, van Oers MH, Schouten HC et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 2009; 113: 1375–1382.

    Article  CAS  PubMed  Google Scholar 

  11. Harned TM, Gaynon P . Relapsed acute lymphoblastic leukemia: current status and future opportunities. Curr Oncol Rep 2008; 10: 453–458.

    Article  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. 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  PubMed  PubMed Central  Google Scholar 

  14. 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  PubMed  PubMed Central  Google Scholar 

  15. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 2005; 19: 1841–1843.

    Article  CAS  PubMed  Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000; 5: 207–216.

    Article  CAS  PubMed  Google Scholar 

  18. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 2000; 5: 197–206.

    Article  CAS  PubMed  Google Scholar 

  19. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004; 82: 341–358.

    Article  CAS  PubMed  Google Scholar 

  20. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005; 435: 959–963.

    Article  CAS  PubMed  Google Scholar 

  21. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279: 12876–12882.

    Article  CAS  PubMed  Google Scholar 

  22. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003; 278: 46107–46116.

    Article  CAS  PubMed  Google Scholar 

  23. Deangelo D, Stone R, Silverman L, Stock W, Attar E, Fearen I et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 2006 ASCO Annu Meet Proc Part I 2006; 24: 6585.

    Google Scholar 

  24. 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  PubMed  PubMed Central  Google Scholar 

  25. 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  PubMed  PubMed Central  Google Scholar 

  26. Margolin AA, Palomero T, Sumazin P, Califano A, Ferrando AA, Stolovitzky G . ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes. Proc Natl Acad Sci USA 2009; 106: 244–249.

    Article  CAS  PubMed  Google Scholar 

  27. 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  PubMed  Google Scholar 

  28. Tissing WJ, Meijerink JP, den Boer ML, Pieters R . Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia 2003; 17: 17–25.

    Article  CAS  PubMed  Google Scholar 

  29. Kaspers GJ, Pieters R, Klumper E, De Waal FC, Veerman AJ . Glucocorticoid resistance in childhood leukemia. Leuk Lymphoma 1994; 13: 187–201.

    Article  CAS  PubMed  Google Scholar 

  30. Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999; 94: 1209–1217.

    CAS  PubMed  Google Scholar 

  31. Schrappe M, Arico M, Harbott J, Biondi A, Zimmermann M, Conter V et al. Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 1998; 92: 2730–2741.

    CAS  PubMed  Google Scholar 

  32. Klumper E, Pieters R, Veerman AJ, Huismans DR, Loonen AH, Hahlen K et al. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood 1995; 86: 3861–3868.

    CAS  PubMed  Google Scholar 

  33. Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R . In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood 1997; 89: 2959–2965.

    CAS  PubMed  Google Scholar 

  34. Kaspers GJ, Wijnands JJ, Hartmann R, Huismans L, Loonen AH, Stackelberg A et al. Immunophenotypic cell lineage and in vitro cellular drug resistance in childhood relapsed acute lymphoblastic leukaemia. Eur J Cancer 2005; 41: 1300–1303.

    Article  CAS  PubMed  Google Scholar 

  35. Aster JC, Pear WS, Blacklow SC . Notch Signaling in Leukemia. Annu Rev Pathol 2008; 3: 587–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Deftos ML, He YW, Ojala EW, Bevan MJ . Correlating notch signaling with thymocyte maturation. Immunity 1998; 9: 777–786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eisen LP, Elsasser MS, Harmon JM . Positive regulation of the glucocorticoid receptor in human T-cells sensitive to the cytolytic effects of glucocorticoids. J Biol Chem 1988; 263: 12044–12048.

    CAS  PubMed  Google Scholar 

  38. Ramdas J, Liu W, Harmon JM . Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res 1999; 59: 1378–1385.

    CAS  PubMed  Google Scholar 

  39. Levine EG, Peterson BA, Smith KA, Hurd DD, Bloomfield CD . Glucocorticoid receptors in chronic lymphocytic leukemia. Leuk Res 1985; 9: 993–999.

    Article  CAS  PubMed  Google Scholar 

  40. Leventhal BG . Glucocorticoid receptors in lymphoid tumors. Cancer Res 1981; 41 (11 Part 2): 4861–4862.

    CAS  PubMed  Google Scholar 

  41. Pedersen KB, Vedeckis WV . Quantification and glucocorticoid regulation of glucocorticoid receptor transcripts in two human leukemic cell lines. Biochemistry 2003; 42: 10978–10990.

    Article  CAS  PubMed  Google Scholar 

  42. Pedersen KB, Geng CD, Vedeckis WV . Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line. Biochemistry 2004; 43: 10851–10858.

    Article  CAS  PubMed  Google Scholar 

  43. Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW et al. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 2002; 129: 2619–2628.

    CAS  PubMed  Google Scholar 

  44. Wei D, Kanai M, Huang S, Xie K . Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis 2006; 27: 23–31.

    Article  CAS  PubMed  Google Scholar 

  45. Tissing WJ, Meijerink JP, Brinkhof B, Broekhuis MJ, Menezes RX, den Boer ML et al. Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL. Blood 2006; 108: 1045–1049.

    Article  CAS  PubMed  Google Scholar 

  46. Asnafi V, Buzyn A, Le Noir S, Baleydier F, Simon A, Beldjord K et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favourable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a GRAALL study. Blood 2008, 23 December 2008 [E-pub ahead of print].

  47. Stylianou S, Clarke RB, Brennan K . Aberrant activation of notch signaling in human breast cancer. Cancer Res 2006; 66: 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  48. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 2005; 65: 2353–2363.

    Article  CAS  PubMed  Google Scholar 

  49. Pahlman S, Stockhausen MT, Fredlund E, Axelson H . Notch signaling in neuroblastoma. Semin Cancer Biol 2004; 14: 365–373.

    Article  CAS  PubMed  Google Scholar 

  50. Kimura K, Satoh K, Kanno A, Hamada S, Hirota M, Endoh M et al. Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci 2007; 98: 155–162.

    Article  CAS  PubMed  Google Scholar 

  51. Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH . Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006; 5: 483–493.

    Article  CAS  PubMed  Google Scholar 

  52. Konishi J, Kawaguchi KS, Vo H, Haruki N, Gonzalez A, Carbone DP et al. Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 2007; 67: 8051–8057.

    Article  CAS  PubMed  Google Scholar 

  53. Phng LK, Gerhardt H . Angiogenesis: A Team Effort Coordinated by Notch. Dev Cell 2009; 16: 196–208.

    Article  CAS  PubMed  Google Scholar 

  54. Thurston G, Kitajewski J . VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 2008; 99: 1204–1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dufraine J, Funahashi Y, Kitajewski J . Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 2008; 27: 5132–5137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 2007; 67: 11244–11253.

    Article  CAS  PubMed  Google Scholar 

  57. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006; 444: 1083–1087.

    Article  CAS  PubMed  Google Scholar 

  58. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006; 444: 1032–1037.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by the NIH (grants R01CA120196 and R01CA129382), the Leukemia and Lymphoma Society (grants 1287-08 and 6237-08) (AF) and Fondo de Investigacion Sanitaria (grant CD07/00033) (PJR). Adolfo Ferrando is a Leukemia and Lymphoma Society Scholar.

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Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, NY, USA

    P J Real & A A Ferrando

  2. Andalusian Stem Cell Bank, Centro de Investigacion Biomedica, Granada, Spain

    P J Real

  3. Department of Pathology, Columbia University Medical Center, New York, NY, USA

    A A Ferrando

  4. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

    A A Ferrando

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Correspondence to A A Ferrando.

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Real, P., Ferrando, A. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23, 1374–1377 (2009). https://doi.org/10.1038/leu.2009.75

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