Myeloid Proliferations of Down Syndrome

  • Lee J. McGhanEmail author
  • Maria A. Proytcheva
Part of the Atlas of Anatomic Pathology book series (AAP)


Individuals with Down syndrome (DS) have a markedly increased risk of developing unique myeloid proliferations such as transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML-DS) [1, 2]. These proliferations occur in the first 3 years of life and are a result of several transforming genetic events that arise during the fetal and newborn period. The initial event, an additional chromosome 21, leads to increased megakaryocytic proliferation in the fetal liver. Subsequent mutation of GATA-binding protein 1 (GATA1) results in the development of TAM. Further acquisition of additional mutations of epigenetic regulators and common signaling pathways such as JAK family kinases, MPL, and multiple RAS pathway genes leads to the transformation to MS-DS [3].


Down syndrome Transient abnormal myelopoiesis Myeloid leukemia associated with Down syndrome Acute megakaryoblastic leukemia GATA1 mutation 


  1. 1.
    Mateos MK, Barbaric D, Byatt SA, Sutton R, Marshall GM. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl Pediatr. 2015;4:76–92.PubMedPubMedCentralGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedGoogle Scholar
  4. 4.
    Cantor AB. Myeloid proliferations associated with Down syndrome. J Hematop. 2015;8:169–76.CrossRefPubMedGoogle Scholar
  5. 5.
    Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I. Transient abnormal myelopoiesis and AML in Down syndrome: an update. Curr Hematol Malig Rep. 2016;11:333–41.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bombery M, Vergillo J. Transient abnormal myelopoiesis in neonates: GATA get the diagnosis. Arch Pathol Lab Med. 2014;138:1302–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, et al. Oxford-Imperial Down Syndrome Cohort Study Group. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Blink M, van den Heuvel-Eibrink MM, Aalbers AM, Balgobind BV, Hollink IH, Meijerink JP, et al. High frequency of copy number alterations in myeloid leukemias of Down syndrome. Br J Haematol. 2012;158:800–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Blink M, Zimmermann M, von Neuhoff C, Reinhardt D, de Haas V, Hasle H, et al. Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica. 2014;99:299–307.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Blink M, Buitenkamp TD, van den Heuvel-Eibrink MM, Danen-van Oorschot AA, de Haas V, Reinhardt D, et al. Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia. Leukemia. 2011;25:1365–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Walters DK, Mercher T, TL G, O'Hare T, Tyner JW, Loriaux M, et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell. 2006;10:65–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu SN, Perez C, et al. Activating mutations in human acute megakaryoblastic leukemia. Blood. 2008;112:4220–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Kivivuori SM, Rajantie J, Siimes MA. Peripheral blood cell counts in infants with Down’s syndrome. Clin Genet. 1996;49:15–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Akin K. Macrocytosis and leukopenia in Down’s syndrome. JAMA. 1988;259:842.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Arizona/Banner University Medical CenterTucsonUSA

Personalised recommendations