Down Syndrome and Acute Myeloid Leukemia: An Unique Genetic Sensitivity to Chemotherapy

  • Jeffrey W. Taub
  • Yubin Ge
  • Yaddanapudi Ravindranath


Following the first description of leukemia in a Down syndrome (DS) child in 1930 (Brewster and Cannon 1930), a national survey in 1957 confirmed that DS individuals had an increased risk of developing leukemia (Krivit and Good 1957). It has been estimated that DS children have a 10 to 20-fold increased risk of developing both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) compared to nonDS children (Taub 2001). A Danish population-based study reported that the cumulative risk of developing leukemia in DS children by the age of 5 was 2.1%, and there was an approximately fourfold higher standardized incidence ratio of AML compared to ALL (Hasle et al. 2000). The Nordic Society of Pediatric Hematology and Oncology (NOPHO) cooperative group reported that DS children with ALL and AML comprised 2.1% and 14%, respectively, of total childhood leukemia cases (Zeller et al. 2005). In the Children’s Cancer Group (CCG) 2891 study, 15% of the AML patients had DS, indicating that DS children comprise one of the largest subgroup of AML patients.


Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Down Syndrome Acute Myeloid Leukemia Patient Down Syndrome Patient 



Supported by grants RO1 CA92308 and CA120772 from the National Cancer Institute, the Leukemia and Lymphoma Society, The Elana Fund, The Ring Screw Textron Chair in Pediatric Cancer Research and The Georgie Ginopolis Chair for Pediatric Cancer and Hematology.


  1. Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., O’Marcaigh, A., Wynn, R., Stevens, R., Addison, M., King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. 2004. Natural history of GATA1 mutations in Down Syndrome. Blood 103:2480–2489.PubMedCrossRefGoogle Scholar
  2. Al-Ahmari, A., Shah, N., Sung, L., Zipursky, A., Hitzler, J. 2006. Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome. Br J Haematol 133:646–648.PubMedCrossRefGoogle Scholar
  3. Athale, U.H., Razzouk, B.I., Raimondi, S.C., Tong, X., Behm, F.G., Head, D.R., Srivastava, D.K., Rubnitz, J.E., Bowman, L., Pui, C.H., Ribeiro, R.C. 2001. Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution’s experience. Blood 97:3727–3732.PubMedCrossRefGoogle Scholar
  4. Barnard, D.R., Alonzo, T.A., Gerbing, R.B., Lange, B., Woods, W.G. 2007. Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children’s Oncology Group. Pediatr Blood Cancer 49:17–22.PubMedCrossRefGoogle Scholar
  5. Bourquin, J.P., Subramanian, A., Langebrake, C., Reinhardt, D., Bernard, O., Ballerini, P., Baruchel, A., Cave, H., Dastugue, N., Hasle, H., Kaspers, G.L., Lessard, M., Michaux, L., Vyas, P., van Wering, E., Zwaan, C.M., Golub, T.R., Orkin, S.H. 2006. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA 103:3339–3344.PubMedCrossRefGoogle Scholar
  6. Brewster, H.F., Cannon, H.E. 1930. Acute lymphatic leukemia: report of a case in an eleventh month mongolian idiot. New Orleans Med Surg J 82:872–873.Google Scholar
  7. Busciglio, J., Yankner, B.A. 1995. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378:776–779.PubMedCrossRefGoogle Scholar
  8. Chien, M.T., Buck, S., Johnson, R.M., Stout, M., Ravindranath, Y. 2004. Increased generation of reactive oxygen species correlates with cytotoxicity in Acute Myeloid Leukemia (AML) of Down Syndrome and is augmented by cytotoxic agents affecting the mitochondrial electron transport chain. Pediatr Res 55: (abstract 1681).Google Scholar
  9. Creutzig, U., Reinhardt, D., Diekamp, S., Dworzak, M., Stary, J., Zimmermann, M. 2005. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19:1355–1360.PubMedCrossRefGoogle Scholar
  10. de Haann, J.B., Wolvetang, E.J., Cristiano, F., Iannello, R., Bladier, C., Kelner, M.J., Kola, I. 1997. Reactive oxygen species and their contribution to pathology in Down syndrome. Adv Pharmacol 38:379–402.CrossRefGoogle Scholar
  11. Duchayne, E., Fenneteau, O., Pages, M.P., Sainty, D., Arnoulet, C., Dastugue, N., Garand, R., Flandrin, G., Groupe Francais d’Hematologie Cellulaire, Groupe Francais de Cytogenetique Hematologique. 2003. Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Francais d’Hematologie Cellulaire (GFHC). Leuk Lymphoma 44:49–58.PubMedCrossRefGoogle Scholar
  12. Edwards, H., Xie, C., LaFiura, K. M., Dombkowski, A., Buck, S., Boerner, J., Taub, J. W., Matherly, L. H., Ge, Y. 2009. RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia. Blood 114:2744–2752.PubMedCrossRefGoogle Scholar
  13. Frost, B.M., Gustafsson, G., Larsson, R., Nygren, P., Lonnerholm, G. 2000. Cellular cytotoxic drug sensitivity in children with acute leukemia and Down’s syndrome: an explanation to differences in clinical outcome? Leukemia 14:943–944.PubMedCrossRefGoogle Scholar
  14. Gamis, A.S., Woods, W.G., Alonzo, T.A., Buxton, A., Lange, B., Barnard, D.R., Gold, S., Smith, F.O. Children’s Cancer Group Study 2891. 2003. Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children’s Cancer Group Study 2891. J Clin Oncol 21:3415–3422.PubMedCrossRefGoogle Scholar
  15. Garrido, S.M., Appelbaum, F.R., Willman, C.L., Banker, D.E. 2001. Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Exp Hematol 29:448–457.PubMedCrossRefGoogle Scholar
  16. Ge, Y., Jensen, T., James, S.J., Becton, D.L., Massey, G.V., Weinstein, H.J., Ravindranath, Y., Matherly, L.H., Taub, J.W. 2002. High frequency of the 844 ins 68 cystathionine-β-synthase gene variant in Down Syndrome children with acute myeloid leukemia. Leukemia 16:2339–2341.PubMedCrossRefGoogle Scholar
  17. Ge, Y., Jensen, T.L., Matherly, L.H., Taub, J.W. 2003. Transcriptional regulation of the cystathionine-ß-synthase gene in Down syndrome and non-Down syndrome megakaryocytic leukemia cell lines. Blood 101:1551–1557.PubMedCrossRefGoogle Scholar
  18. Ge, Y., Jensen, T.L., Stout, M.L., Flatley, R.M., Grohar, P.J., Ravindranath, Y., Matherly, L.H., Taub, J.W. 2004. The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines. Cancer Res 64:728–735.PubMedCrossRefGoogle Scholar
  19. Ge, Y., Stout, M.L., Tatman, D.A., Jensen, T.L., Buck, S., Thomas, R.L., Ravindranath, Y., Matherly, L.H., Taub, J.W. 2005. GATA1, cytidine deaminase and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Institute 97:226–231.CrossRefGoogle Scholar
  20. Ge, Y., Dombkowski, A.A., LaFiura, K.M., Tatman, D., Yedidi, R.S., Stout, M.L., Buck, S.A., Massey, G., Becton, D.L., Weinstein, H.J., Ravindranath, Y., Matherly, L.H., Taub, J.W. 2006. Differential gene expression, GATA1 target genes and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia. Blood 107:1570–1581.PubMedCrossRefGoogle Scholar
  21. Hasle, H., Clemmensen, I.H., Mikkelsen, M. 2000. Risks of leukaemia and solid tumours individuals with Down’s syndrome. Lancet 355:165–169.PubMedCrossRefGoogle Scholar
  22. Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W., Zipursky, A. 2003. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101:4301–4304.PubMedCrossRefGoogle Scholar
  23. Ishikawa, J., Kaisho, T., Tomizawa, H., Lee, B.O., Kobune, Y., Inazawa, J., Oritani, K., Itoh, M., Ochi, T., Ishihara, K., Hirano, T. 1995. Molecular cloning and chromosomal mapping of a bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth. Genomics 26:527–534.PubMedCrossRefGoogle Scholar
  24. Iwamoto, S., Mihara, K., Downing, J.R., Pui, C.H., Campana, D. 2007. Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest 117:1049–1057.PubMedCrossRefGoogle Scholar
  25. Konopleva, M., Konoplew, S., Hu, W., Zaritskey, A.Y., Afanasiev, B.V., Andreeff, M. 2002. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 16:1713–1724.PubMedCrossRefGoogle Scholar
  26. Krischer, J.P., Epstein, S., Cuthbertson, D.D., Goorin, A.M., Epstein, M.L., Lipshultz, S.E. 1997. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15:1544–1552.PubMedGoogle Scholar
  27. Krivit, W., Good, R.A. 1957. Simultaneous occurrence of mongolism and leukemia. Am J Dis Child 94:289–293.Google Scholar
  28. Kudo, K., Kojima, S., Tabuchi, K., Ishii, E., Yabe, H., Tawa, A., Imaizumi, M., Hanada, R., Hamamoto, K., Kobayashi, R., Morimoto, A., Nakayama, H., Tsuchiya, S., Tsuchida, M., Horibe, K. 2005. Results of the Japanese Childhood Acute Myeloid Leukemia 99 protocol for Down Syndrome and Acute Myeloid Leukemia. Blood 106: abstract 276.Google Scholar
  29. Lange, B.J., Kobrinsky, N., Barnard, D.R., Arthur, D.C., Buckley, J.D., Howells, W.B., Gold, S., Sanders, J., Neudorf, S., Smith, F.O., Woods, W.G. 1998. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. Blood 91:608–615.PubMedGoogle Scholar
  30. Lehrnbecher, T., Varwig, D., Kaiser, J., Reinhardt, D., Klinebiel, T., Creutzig, U. 2004. Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 18:72–77.PubMedCrossRefGoogle Scholar
  31. Lie, S.O., Abrahamsson, J., Clausen, N., Forestier, E., Hasle, H., Hovi, L., Jonmundsson, G., Mellander, L., Siimes, M.A., Yssing, M., Zeller, B., Gustafsson, G.; Nordic Society of Pediatric Hematology and Oncology (NOPHO), AML Study Group. 2005. Long-term results in children with AML: NOPHO-AML Study Group – report of three consecutive trials. Leukemia 19:2090–2100.PubMedCrossRefGoogle Scholar
  32. Loew, T.W., Gamis, A., Smith, F.O., Massey, G.V., Woods, W.G., Hilden, J.M., Lange, B., Alonzo, T.A., Chang, M., Gerbing, R.B. 2004. Down syndrome patients with relapsed acute myelogenous leukemia. Blood 104: (abstract 4526).Google Scholar
  33. Muntean, A.G., Ge, Y., Taub, J.W., Crispino, J.D. 2006. Transcription factor GATA-1 and Down syndrome leukemogenesis. Leuk Lymphoma 47:986–997.PubMedCrossRefGoogle Scholar
  34. Newman, E.M., Villacorte, D.G., Testi, A.M., Krance, R.A., Harris, M.B., Ravindranath, Y., Pinkel, D. 1990. Biochemical interactions between methotrexate and 1-beta-D-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study. Cancer Chemother Pharmacol 27:60–66.PubMedCrossRefGoogle Scholar
  35. O’Brien, M., Taub, J., Stine, K., Chang, M., Ravindranath, Y., Becton, D., Dahl, G.V. 2006. Excessive cardiotoxicity despite excellent leukemia-free survival for pediatric patients with Down syndrome and acute myeloid leukemia: results from POG (Pediatric Oncology Group) protocol 9421. Blood 108: (abstract 559).Google Scholar
  36. Ohtomo, T., Sugamata, Y., Ozaki, Y., Ono, K., Yoshimura, Y., Kawai, S., Koishihara, Y., Ozaki, S., Kosaka, M., Hirano, T., Tsuchiya, M. 1999. Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. Biochem Biophys Res Commun 258:583–591.PubMedCrossRefGoogle Scholar
  37. Oki, Y., Kantarjian, H.M., Zhou, X., Cortes, J., Faderl, S., Verstovsek, S., O’Brien, S., Koller, C., Beran, M., Bekele, B.N., Pierce, S., Thomas, D., Ravandi, F., Wierda, W.G., Giles, F., Ferrajoli, A., Jabbour, E., Keating, M.J., Bueso-Ramos, C.E., Estey, E., Garcia-Manero, G. 2006. Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center. Blood 107:880–884.PubMedCrossRefGoogle Scholar
  38. Pagano, L., Pulsoni, A., Vignetti, M., Mele, L., Fianchi, L., Petti, M.C., Mirto, S., Falcucci, P., Fazi, P., Broccia, G., Specchia, G., Di Raimondo, F., Pacilli, L., Leoni, P., Ladogana, S., Gallo, E., Venditti, A., Avanzi, G., Camera, A., Liso, V., Leone, G., Mandelli, F. 2002. Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16:1622–1626.PubMedCrossRefGoogle Scholar
  39. Peeters, M., Poon, A. 1987. Down syndrome and leukemia: unusual clinical aspects and unexpected methotrexate sensitivity. Eur J Pediatr 146:416–422.PubMedCrossRefGoogle Scholar
  40. Rainis, L., Bercovich, D., Strehl, S., Teigler-Schlegel, A., Stark, B., Trka, J., Amariglio, N., Biondi, A., Muler, I., Rechavi, G., Kempski, H., Haas, O.A., Izraeli, S. 2003. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102:981–986.PubMedCrossRefGoogle Scholar
  41. Rao, A., Hills, R.K., Stiller, C., Gibson, B.E., Graaf, S.S., Hann, I.M., O’Marcaigh, A., Wheatley, K., Webb, D.K. 2006. Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. Br J Haematol 132:576–583.PubMedCrossRefGoogle Scholar
  42. Ravindranath, Y., Abella, E., Krischer, J., Wiley, J., Inoue, S., Harris, M., Chauvenet, A., Alvarado, C.S., Dubowy, R., Ritchey, A.K., Land, V., Steuber, C.P., Weinstein, H.J. 1992. Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML study 8498. Blood 80:2210–2214.PubMedGoogle Scholar
  43. Ravindranath, Y., Yeager, A.M., Chang, M.N., Steuber, C.P., Krischer, J., Graham-Pole, J., Carroll, A., Inoue, S., Camitta, B., Weinstein, J.H. 1996. Acute myeloid leukemia in children: a randomized comparative study of purged autologous bone marrow transplantation versus intensive multiagent consolidation chemotherapy in first remission (Pediatric Oncology Group Study-POG 8821). N Engl J Med 334:1428–1434.PubMedCrossRefGoogle Scholar
  44. Ravindranath, Y., Chang, M., Steuber, C.P., Becton, D., Dahl, G., Civin, C., Camitta, B., Carroll, A., Raimondi, S.C., Weinstein, H.J., Pediatric Oncology Group. 2005. Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000. Leukemia 19:2101–2116.PubMedCrossRefGoogle Scholar
  45. Reinhardt, D., Diekamp, S., Langebrake, C., Ritter, J., Stary, J., Dworzak, M., Schrauder, A., Zimmermann, M., Fleischhack, G., Ludwig, W.D., Harbott, J., Creutzig, U. 2005. Acute megakaryoblastic leukemia in children and adolescents, excluding Down’s syndrome: improved outcome with intensified induction treatment. Leukemia 19:1495–1496.PubMedCrossRefGoogle Scholar
  46. Ruiz-Argüelles, G.J., Lobato-Mendizábal, E., San-Miguel, J.F., González, M., Caballero, M.D., Ruiz-Argüelles, A., Orfao, A., Gómez-Almaguer, D., Vidriales, B., Ruiz-Reyes, G., López-Borrasca, L. 1992. Long-term treatment results for acute megakaryoblastic leukaemia patients: a multicentre study. Br J Haematol 82:671–675.PubMedCrossRefGoogle Scholar
  47. Savasan, S., Buck, S., Raimondi, S.C., Becton, D.L., Weinstein, H., Chang, M., Ravindranath, Y. 2006. CD36 (thrombospondin receptor) expression in childhood acute megakaryoblastic leukemia: in vitro drug sensitivity and outcome. Leuk Lymphoma 47:2076–2083.PubMedCrossRefGoogle Scholar
  48. Shimamoto, T., Ohyashiki, K., Ohyashiki, J.H., Kawakubo, K., Fujimura, T., Iwama, H., Nakazawa, S., Toyama, K. 1995. The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia. Blood 86:3173–3180.PubMedGoogle Scholar
  49. Tallman, M.S., Neuberg, D., Bennett, J.M., Francois, C.J., Paietta, E., Wiernik, P.H., Dewald, G., Cassileth, P.A., Oken, M.M., Rowe, J.M. 2000. Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood 96:2405–2411.PubMedGoogle Scholar
  50. Taub, J.W. 2001. Relationship of chromosome 21 and acute leukemia in children with Down syndrome. J Pediatr Hematol Oncol 23:175–178.PubMedCrossRefGoogle Scholar
  51. Taub, J.W., Ge, Y. 2005. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44:33–39.PubMedCrossRefGoogle Scholar
  52. Taub, J.W., Matherly, L.H., Stout, M.L., Buck, S.A., Gurney, J.G., Ravindranath, Y. 1996. Enhanced metabolism of 1-ß-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87:3395–3403.PubMedGoogle Scholar
  53. Taub, J.W., Huang, X., Matherly, L.H., Stout, M.L., Buck, S.A., Massey, G.V., Becton, D.L., Chang, M.N., Weinstein, H.J., Ravindranath, Y. 1999. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 94:1393–1400.PubMedGoogle Scholar
  54. Taub, J.W., Huang, X., Ge, Y., Dutcher, J.A., Stout, M.L., Mohammad, R.M., Ravindranath, Y., Matherly, L.H. 2000. Cystathionine-ß-synthase cDNA transfection alters the sensitivity and metabolism of cytosine arabinoside in CCRF-CEM leukemia cells in vitro and in vivo: a model of leukemia in Down syndrome. Cancer Res 60:6421–6426.PubMedGoogle Scholar
  55. Wechsler, J., Greene, M., McDevitt, M.A., Anastasi, J., Karp, J.E., LeBeau, M.M., Crispino, J.D. 2002. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152.PubMedCrossRefGoogle Scholar
  56. Whitlock, J.A. 2006. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135:595–602.PubMedCrossRefGoogle Scholar
  57. Zeller, B., Gustafsson, G., Forestier, E., Abrahamsson, J., Clausen, N., Heldrup, J., Hovi, L., Jonmundsson, G., Lie, S.O., Glomstein, A., Hasle, H. 2005. Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128:797–804.PubMedCrossRefGoogle Scholar
  58. Zipursky, A., Thorner, P., De Harven, E., Christensen, H., Doyle, J. 1994. Myelodysplasia and acute megakaryoblastic leukemia in Down’s syndrome. Leuk Res 18:163–171.PubMedCrossRefGoogle Scholar
  59. Zubizarreta, P., Felice, M.S., Alfaro, E., Fraquelli, L., Casak, S., Quinteros, R., Cygler, A., Gallego, M., Perez, L.E., Sackmann-Muriel, F. 1998. Acute myelogenous leukemia in Down’s syndrome: report of a single pediatric institution using a BFM treatment strategy. Leuk Res 22:465–472.PubMedCrossRefGoogle Scholar
  60. Zwaan, C.M., Kaspers, G.J., Pieters, R., Hahlen, K., Janka-Schaub, G.E., van Zantwijk, C.H., Huismans, D.R., de Vries, E., Rots, M.G., Peters, G.J., Jansen, G., Creutzig, U., Veerman, A.J. 2002. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 99:245–251.PubMedCrossRefGoogle Scholar
  61. Zweegman, S., Veenhof, M.A., Debili, N., Schuurhuis, G.J., Huijgens, P.C., Drager, A.M. 1999. Megakaryocytic differentiation of human progenitor cells is negatively influenced by direct contact with stroma. Leukemia 13:935–943.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jeffrey W. Taub
    • 1
    • 2
    • 3
  • Yubin Ge
  • Yaddanapudi Ravindranath
  1. 1.Division of Hematology/OncologyChildren’s Hospital of MichiganDetroitUSA
  2. 2.Department of PediatricsWayne State University School of MedicineDetroitUSA
  3. 3.Developmental and Therapeutics ProgramBarbara Ann Karmanos Cancer InstituteDetroitUSA

Personalised recommendations