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.

Clinical and biological aspects of myeloid leukemia in Down syndrome

Abstract

Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal myelopoiesis (TAM), which is self-limited expansion of fetal liver-derived megakaryocyte progenitors. An array of international studies has led to consensus in treating ML-DS with reduced-intensity chemotherapy, leading to excellent outcomes. In addition, studies performed in the past 20 years have revealed many of the genetic and epigenetic features of the tumors, including GATA1 mutations that are arguably associated with all cases of both TAM and ML-DS. Despite these advances in understanding the clinical and biological aspects of ML-DS, little is known about the mechanisms of relapse. Upon relapse, patients face a poor outcome, and there is no consensus on treatment. Future studies need to be focused on this challenging aspect of leukemia in children with DS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline of events during ML-DS progression.
Fig. 2: Clonal evolution of ML-DS and relapse.

References

  1. 1.

    Krivit W, Good RA. Simultaneous occurrence of mongolism and leukemia; report of a nationwide survey. AMA J Dis Child. 1957;94:289–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 2000;355:165–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Patja K, Pukkala E, Sund R, Iivanainen M, Kaski M. Cancer incidence of persons with Down syndrome in Finland: a population-based study. Int J Cancer. 2006;118:1769–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Sullivan SG, Hussain R, Glasson EJ, Bittles AH. The profile and incidence of cancer in Down syndrome. J Intellect Disabil Res. 2007;51:228–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Cancers and immune related diseases associated with Down’s syndrome: a record linkage study. Arch Dis Child. 2004;89:1014–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Marlow EC, Ducore J, Kwan ML, Cheng SY, Bowles EJA, Greenlee RT, et al. Leukemia risk in a cohort of 3.9 million children with and without down syndrome. J Pediatr. 2021;234:172–180.e3.

  7. 7.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, et al. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 2013;122:3908–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Zipursky A, Thorner P, De Harven E, Christensen H, Doyle J. Myelodysplasia and acute megakaryoblastic leukemia in Down’s syndrome. Leuk Res. 1994;18:163–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Langebrake C, Creutzig U, Reinhardt D. Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. Klin Padiatr. 2005;217:126–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Karandikar NJ, Aquino DB, McKenna RW, Kroft SH. Transient myeloproliferative disorder and acute myeloid leukemia in Down syndrome. An immunophenotypic analysis. Am J Clin Pathol. 2001;116:204–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Goemans BF, Noort S, Blink M, Wang YD, Peters S, van Wouwe JP, et al. Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia. Leukemia. 2021;35:2403–6.

  13. 13.

    Tunstall O, Bhatnagar N, James B, Norton A, O’Marcaigh AS, Watts T, et al. Guidelines for the investigation and management of transient leukaemia of Down syndrome. Br J Haematol. 2018;182:200–11.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Pine SR, Guo Q, Yin C, Jayabose S, Druschel CM, Sandoval C. Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. Blood 2007;110:2128–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Gamis AS, Alonzo TA, Gerbing RB, Hilden JM, Sorrell AD, Sharma M, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the children’s oncology group study A2971. Blood 2011;118:6752–9. quiz 996.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008;111:2991–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Massey GV, Zipursky A, Chang MN, Doyle JJ, Nasim S, Taub JW, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): children’s oncology group (COG) study POG-9481. Blood 2006;107:4606–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Muramatsu H, Kato K, Watanabe N, Matsumoto K, Nakamura T, Horikoshi Y, et al. Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol. 2008;142:610–5.

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Yamato G, Deguchi T, Terui K, Toki T, Watanabe T, Imaizumi T, et al. Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome. Leukemia. 2021;35:1480–4.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Alford KA, Reinhardt K, Garnett C, Norton A, Böhmer K, von Neuhoff C, et al. Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 2011;118:2222–38.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Flasinski M, Scheibke K, Zimmermann M, Creutzig U, Reinhardt K, Verwer F, et al. Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD prevention 2007 study. Blood Adv. 2018;2:1532–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Zeller B, Gustafsson G, Forestier E, Abrahamsson J, Clausen N, Heldrup J, et al. Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol. 2005;128:797–804.

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Frost BM, Gustafsson G, Larsson R, Nygren P, Lönnerholm G. Cellular cytotoxic drug sensitivity in children with acute leukemia and Down’s syndrome: an explanation to differences in clinical outcome? Leukemia 2000;14:943–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Taub JW, Matherly LH, Stout ML, Buck SA, Gurney JG, Ravindranath Y. Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 1996;87:3395–403.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Zwaan CM, Kaspers GJ, Pieters R, Hählen K, Janka-Schaub GE, van Zantwijk CH, et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002;99:245–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Taub JW, Stout ML, Buck SA, Huang X, Vega RA, Becton DL, et al. Myeloblasts from Down syndrome children with acute myeloid leukemia have increased in vitro sensitivity to cytosine arabinoside and daunorubicin. Leukemia 1997;11:1594–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Klingebiel T, Creutzig U. Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 2004;18:72–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Ravindranath Y, Abella E, Krischer JP, Wiley J, Inoue S, Harris M, et al. Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on pediatric oncology group AML study 8498. Blood 1992;80:2210–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Hassler A, Bochennek K, Gilfert J, Perner C, Schöning S, Creutzig U, et al. Infectious complications in children with acute myeloid leukemia and down syndrome: analysis of the prospective multicenter trial AML-BFM 2004. Pediatr Blood Cancer. 2016;63:1070–4.

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    O’Brien MM, Taub JW, Chang MN, Massey GV, Stine KC, Raimondi SC, et al. Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the children’s oncology group study POG 9421. J Clin Oncol. 2008;26:414–20.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  31. 31.

    Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005;19:1355–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Kojima S, Sako M, Kato K, Hosoi G, Sato T, Ohara A, et al. An effective chemotherapeutic regimen for acute myeloid leukemia and myelodysplastic syndrome in children with Down’s syndrome. Leukemia 2000;14:786–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Al-Ahmari A, Shah N, Sung L, Zipursky A, Hitzler J. 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. 2006;133:646–8.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Abildgaard L, Ellebaek E, Gustafsson G, Abrahamsson J, Hovi L, Jonmundsson G, et al. Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: data from 56 children treated on NOPHO-AML protocols and a review of the literature. Ann Hematol. 2006;85:275–80.

    PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Rao A, Hills RK, Stiller C, Gibson BE, de Graaf SS, Hann IM, et al. 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. 2006;132:576–83.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Taga T, Shimomura Y, Horikoshi Y, Ogawa A, Itoh M, Okada M, et al. Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children’s cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer. 2011;57:36–40.

    PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Gamis AS, Woods WG, Alonzo TA, Buxton A, Lange B, Barnard DR, et al. 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. 2003;21:3415–22.

    PubMed  Article  Google Scholar 

  38. 38.

    Sorrell AD, Alonzo TA, Hilden JM, Gerbing RB, Loew TW, Hathaway L, et al. Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on children’s oncology group trial A2971: a report from the children’s oncology group. Cancer 2012;118:4806–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Hasle H, Abrahamsson J, Arola M, Karow A, O’Marcaigh A, Reinhardt D, et al. Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML. Leukemia 2008;22:1428–30.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M, et al. Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with Down syndrome and acute myeloid leukemia: the Japanese childhood AML cooperative study group. J Clin Oncol. 2007;25:5442–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Taga T, Tanaka S, Hasegawa D, Terui K, Toki T, Iwamoto S, et al. Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome. Leukemia. 2021;35:2508–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Uffmann M, Rasche M, Zimmermann M, von Neuhoff C, Creutzig U, Dworzak M, et al. Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 2017;129:3314–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Taub JW, Berman JN, Hitzler JK, Sorrell AD, Lacayo NJ, Mast K, et al. Improved outcomes for myeloid leukemia of Down syndrome: a report from the children’s oncology group AAML0431 trial. Blood 2017;129:3304–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Taga T, Watanabe T, Tomizawa D, Kudo K, Terui K, Moritake H, et al. Preserved high probability of overall survival with significant reduction of chemotherapy for myeloid leukemia in Down Syndrome: A nationwide prospective study in Japan. Pediatr Blood Cancer. 2016;63:248–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Hitzler JK, Alonzo T, Gerbing RB, Beckman A, Hirsch B, Raimondi S, et al. High-dose AraC is essential for the treatment of ML-DS independent of post-induction MRD: Results of COG AAML1531. Blood. 2021; online ahead of print, July 28, 2021.

  46. 46.

    Taga T, Saito AM, Kudo K, Tomizawa D, Terui K, Moritake H, et al. Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 2012;120:1810–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Hitzler JK, He W, Doyle J, Cairo M, Camitta BM, Chan KW, et al. Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transpl. 2013;19:893–7.

    Article  Google Scholar 

  48. 48.

    Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB, et al. 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 1998;91:608–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, Graf N, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from study AML-BFM 2004. Blood 2013;122:37–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36:2684–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Cooper TM, Absalon MJ, Alonzo TA, Gerbing RB, Leger KJ, Hirsch BA, et al. Phase I/II study of CPX-351 followed by fludarabine, cytarabine, and granulocyte-colony stimulating factor for children with relapsed acute myeloid leukemia: a report from the children’s oncology group. J Clin Oncol. 2020;38:2170–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Caldwell JT, Edwards H, Buck SA, Ge Y, Taub JW. Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia. Pediatr Blood Cancer. 2014;61:1767–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Stankov MV, El Khatib M, Kumar Thakur B, Heitmann K, Panayotova-Dimitrova D, Schoening J, et al. Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia 2014;28:577–88.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Scheer C, Kratz C, Witt O, Creutzig U, Reinhardt D, Klusmann JH. Hematologic response to vorinostat treatment in relapsed myeloid leukemia of down syndrome. Pediatr Blood Cancer. 2016;63:1677–9.

    PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Uemura S, Mori T, Nagano C, Takafuji S, Nishimura N, Toki T, et al. Effective response to azacitidine in a child with a second relapse of myeloid leukemia associated with Down syndrome after bone marrow transplantation. Pediatr Blood Cancer. 2018;65:e27414.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Karol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, et al. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study. Lancet Oncol. 2020;21:551–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III children’s oncology group trial AAML0531. J Clin Oncol. 2014;32:3021–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Ling T, Crispino JD. GATA1 mutations in red cell disorders. IUBMB Life. 2020;72:106–18.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, Crispino JD. Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 2003;101:4298–300.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, Trka J, et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003;102:981–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32:148–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Chou ST, Byrska-Bishop M, Tober JM, Yao Y, Vandorn D, Opalinska JB, et al. Trisomy 21-associated defects in human primitive hematopoiesis revealed through induced pluripotent stem cells. Proc Natl Acad Sci USA. 2012;109:17573–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, Brooks JS, et al. Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 2008;112:4503–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Kirsammer G, Jilani S, Liu H, Davis E, Gurbuxani S, Le Beau MM, et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 2008;111:767–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Maclean GA, Menne TF, Guo G, Sanchez DJ, Park IH, Daley GQ, et al. Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc Natl Acad Sci USA. 2012;109:17567–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Malinge S, Bliss-Moreau M, Kirsammer G, Diebold L, Chlon T, Gurbuxani S, et al. Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome. J Clin Invest. 2012;122:948–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Roy A, Cowan G, Mead AJ, Filippi S, Bohn G, Chaidos A, et al. Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci USA. 2012;109:17579–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, et al. Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 2008;112:4507–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Laurent AP, Kotecha RS, Malinge S. Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome. Leukemia. 2020;34:1984–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    McNulty M, Crispino JD. Acute Megakaryocytic Leukemia. Cold Spring Harb Perspect Med. 2020;10:a034884.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Garnett C, Cruz Hernandez D, Vyas P. GATA1 and cooperating mutations in myeloid leukaemia of Down syndrome. IUBMB Life. 2020;72:119–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Grimm J, Heckl D, Klusmann JH. Molecular mechanisms of the genetic predisposition to acute megakaryoblastic leukemia in infants with Down syndrome. Front Oncol. 2021;11:636633.

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Woo AJ, Wieland K, Huang H, Akie TE, Piers T, Kim J, et al. Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation. J Clin Invest. 2013;123:3292–304.

    CAS  PubMed Central  Article  Google Scholar 

  74. 74.

    Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, et al. Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes Dev. 2010;24:1659–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Labuhn M, Perkins K, Matzk S, Varghese L, Garnett C, Papaemmanuil E, et al. Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down Syndrome. Cancer Cell. 2019;36:123–38.e10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet. 2013;45:1293–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Heimbruch KE, Meyer AE, Agrawal P, Viny AD, Rao S. A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML. Neoplasia 2021;23:337–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell. 2015;17:675–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Mullenders J, Aranda-Orgilles B, Lhoumaud P, Keller M, Pae J, Wang K, et al. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. J Exp Med. 2015;212:1833–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Viny AD, Ott CJ, Spitzer B, Rivas M, Meydan C, Papalexi E, et al. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J Exp Med. 2015;212:1819–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Tothova Z, Valton AL, Gorelov RA, Vallurupalli M, Krill-Burger JM, Holmes A, et al. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight. 2021;6:e142149.

    PubMed Central  Article  Google Scholar 

  82. 82.

    Chin CV, Antony J, Ketharnathan S, Labudina A, Gimenez G, Parsons KM, et al. Cohesin mutations are synthetic lethal with stimulation of WNT signaling. Elife. 2020;9:e61405.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Bhansali RS, Rammohan M, Lee P, Laurent AP, Wen Q, Suraneni P, et al. DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3. J Clin Invest. 2021;131:e135937.

    CAS  PubMed Central  Article  Google Scholar 

  84. 84.

    Birger Y, Goldberg L, Chlon TM, Goldenson B, Muler I, Schiby G, et al. Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder. Blood 2013;122:988–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Elagib KE, Racke FK, Mogass M, Khetawat R, Delehanty LL, Goldfarb AN. RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood 2003;101:4333–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Goldfarb AN. Megakaryocytic programming by a transcriptional regulatory loop: A circle connecting RUNX1, GATA-1, and P-TEFb. J Cell Biochem. 2009;107:377–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Langebrake C, Klusmann JH, Wortmann K, Kolar M, Puhlmann U, Reinhardt D. Concomitant aberrant overexpression of RUNX1 and NCAM in regenerating bone marrow of myeloid leukemia of Down’s syndrome. Haematologica 2006;91:1473–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Salek-Ardakani S, Smooha G, de Boer J, Sebire NJ, Morrow M, Rainis L, et al. ERG is a megakaryocytic oncogene. Cancer Res. 2009;69:4665–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Stankiewicz MJ, Crispino JD. ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 2009;113:3337–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Volk A, Liang K, Suraneni P, Li X, Zhao J, Bulic M, et al. A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis. Cancer Cell. 2018;34:707–23.e7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Nižetić D, Groet J. Tumorigenesis in Down’s syndrome: big lessons from a small chromosome. Nat Rev Cancer. 2012;12:721–32.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  92. 92.

    Vukadin L, Kim JH, Park EY, Stone JK, Ungerleider N, Baddoo MC, et al. SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia. Cancer Gene Ther. 2021;28:1000–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Adorno M, Sikandar S, Mitra SS, Kuo A, Nicolis Di Robilant B, Haro-Acosta V, et al. Usp16 contributes to somatic stem-cell defects in Down’s syndrome. Nature 2013;501:380–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Pawlikowski B, Betta ND, Elston T, Williams DA, Olwin BB. Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome. Sci Rep. 2018;8:4309.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Gu Y, Jones AE, Yang W, Liu S, Dai Q, Liu Y, et al. The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function. Proc Natl Acad Sci USA. 2016;113:E51–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Alexandrov PN, Percy ME, Lukiw WJ. Chromosome 21-encoded microRNAs (mRNAs): Impact on Down’s Syndrome and Trisomy-21 linked disease. Cell Mol Neurobiol. 2018;38:769–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Jaiswal A, Reddy SS, Maurya M, Maurya P, Barthwal MK. MicroRNA-99a mimics inhibit M1 macrophage phenotype and adipose tissue inflammation by targeting TNFalpha. Cell Mol Immunol. 2019;16:495–507.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Diao W, Lu L, Li S, Chen J, Zen K, Li L. MicroRNA-125b-5p modulates the inflammatory state of macrophages via targeting B7-H4. Biochem Biophys Res Commun. 2017;491:912–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Yu H, Qin L, Peng Y, Bai W, Wang Z. Exosomes derived from hypertrophic cardiomyocytes induce inflammation in macrophages via miR-155 mediated MAPK pathway. Front Immunol. 2020;11:606045.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Klusmann JH, Li Z, Böhmer K, Maroz A, Koch ML, Emmrich S, et al. miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev. 2010;24:478–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Ahn EE, Higashi T, Yan M, Matsuura S, Hickey CJ, Lo MC, et al. SON protein regulates GATA-2 through transcriptional control of the microRNA 23a~27a~24-2 cluster. J Biol Chem. 2013;288:5381–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Boucher A, Klopfenstein N, Hallas WM, Skibbe J, Appert A, Jang SH, et al. The miR-23a27a24-2 microRNA cluster promotes inflammatory polarization of macrophages. J Immunol. 2021;206:540–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Kurkewich JL, Hansen J, Klopfenstein N, Zhang H, Wood C, Boucher A, et al. The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis. PLoS Genet. 2017;13:e1006887.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

    Su R, Dong L, Zou D, Zhao H, Ren Y, Li F, et al. microRNA-23a, -27a and -24 synergistically regulate JAK1/Stat3 cascade and serve as novel therapeutic targets in human acute erythroid leukemia. Oncogene. 2016;35:6001–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Ben-Ami O, Pencovich N, Lotem J, Levanon D, Groner Y. A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis. Proc Natl Acad Sci USA. 2009;106:238–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Shaham L, Vendramini E, Ge Y, Goren Y, Birger Y, Tijssen MR, et al. MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. Blood 2015;125:1292–301.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Grasedieck S, Sorrentino A, Langer C, Buske C, Döhner H, Mertens D, et al. Circulating microRNAs in hematological diseases: principles, challenges, and perspectives. Blood 2013;121:4977–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Kok VC, Yu CC. Cancer-derived exosomes: Their role in cancer biology and biomarker development. Int J Nanomed. 2020;15:8019–36.

    CAS  Article  Google Scholar 

  109. 109.

    Wang H, Peng R, Wang J, Qin Z, Xue L. Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin Epigenetics. 2018;10:59.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Aguilar-Hernandez MM, Rincon Camacho JC, Galicia Garcia G. Extracellular vesicles and their associated miRNAs as potential prognostic biomarkers in chronic lymphocytic leukemia. Curr Oncol Rep. 2021;23:66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Trino S, Lamorte D, Caivano A, Laurenzana I, Tagliaferri D, Falco G, et al. MicroRNAs as new biomarkers for diagnosis and prognosis, and as potential therapeutic targets in acute myeloid leukemia. Int J Mol Sci. 2018;19:460–85.

    PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Salvi A, Vezzoli M, Busatto S, Paolini L, Faranda T, Abeni E, et al. Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for Down syndrome pathogenesis. Int J Mol Med. 2019;43:2303–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Zaslavsky A, Chou ST, Schadler K, Lieberman A, Pimkin M, Kim YJ, et al. The calcineurin-NFAT pathway negatively regulates megakaryopoiesis. Blood 2013;121:3205–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9:1681–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Liggett LA, Galbraith MD, Smith KP, Sullivan KD, Granrath RE, Enriquez-Estrada B, et al. Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation. Blood Adv. 2021;5:1791–6.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Bolouri H, Farrar JE, Triche T Jr., Ries RE, Lim EL, Alonzo TA, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24:103–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Wagenblast E, Araujo J, Gan OI, Cutting SK, Murison A, Krivdova G, et al. Mapping the cellular origin and early evolution of leukemia in Down syndrome. Science 2021;373:6551.

    Article  CAS  Google Scholar 

  118. 118.

    Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet. 2005;37:613–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Lukes J Jr., Danek P, Alejo-Valle O, Potuckova E, Gahura O, Heckl D, et al. Chromosome 21 gain is dispensable for transient myeloproliferative disorder driven by a novel GATA1 mutation. Leukemia 2020;34:2503–8.

    PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 2020;587:477–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Petti AA, Williams SR, Miller CA, Fiddes IT, Srivatsan SN, Chen DY, et al. A general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing. Nat Commun. 2019;10:3660.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Stetson LC, Balasubramanian D, Ribeiro SP, Stefan T, Gupta K, Xu X, et al. Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression. Leukemia. 2021; Online ahead of print July 9, 2021.

Download references

Acknowledgements

This review was supported in part by a grant from the NIH (CA101774 to JDC and T32CA236748 to ACB). JEF and KJC are supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA021765. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided by St. Jude /ALSAC.

Author information

Affiliations

Authors

Contributions

ACB, KJC, JEF, and JDC wrote the review.

Corresponding authors

Correspondence to John D. Crispino or Jamie E. Flerlage.

Ethics declarations

Competing interests

Jamie Flerlage receives research funding from Seattle Genetics. The other authors declare no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Boucher, A.C., Caldwell, K.J., Crispino, J.D. et al. Clinical and biological aspects of myeloid leukemia in Down syndrome. Leukemia (2021). https://doi.org/10.1038/s41375-021-01414-y

Download citation

Search

Quick links