Pediatric Myeloid proliferation with Down syndrome

2023-06-25   Sheng Xiao, MD , Chunxiao Yang  

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2. Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

Patients with Down syndrome are at a 20- to 50-fold higher risk of developing leukemia compared to the general population, specifically acute megakaryoblastic leukemia (AMKL), which occurs 500 times more frequently in Down syndrome patients.1 Additionally, approximately 25% of these patients experience transient abnormal myelopoiesis (TAM). The precise oncogenic mechanism underlying the link between trisomy 21 and leukemia remains uncertain. However, it is known that several oncogenes critical to hematopoiesis located on chromosome 21, including DYRK1A, ETS2, ERG, and RUNX1.2 In addition, a detailed mapping study in a Down syndrome patient with TAM and partial trisomy 21 revealed a 10 Mb critical region at 21q22.12-21q22.3, encompassing DYRK1A, ERG, and ETS genes.3 Subsequent studies demonstrated that DYRK1A promotes megakaryoblastic leukemia in a murine model of Down syndrome.4,5 Interestingly and surprisingly, despite the increased risk of hematopoietic malignancies, patients with Down syndrome paradoxically exhibit a significantly lower incidence of most solid tumors.6,7 This phenomenon could be attributed to the Down syndrome candidate region 1 (DSCR1) gene that encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signaling.8 Angiogenesis has been extensively demonstrated to play a crucial role in the development of solid tumors,9 but its significance may be less pronounced in leukemia, as hematopoietic tissues typically have an abundant blood supply of nutrition and oxygen.
Pediatric Myeloid proliferations associated with Down syndromeGenetic marker(s)
Transient abnormal myelopoiesis associated with Down syndrome (TAM)The dominant driver gene is the GATA1 mutation. In addition, constitutional trisomy 21 is present by definition in this disease.>90% TAM resolves spontaneously in 2-3 months without treatment, and 20% of symptomatic TAM may later develop ML-DS.10
Myeloid leukaemia associated with Down syndrome (ML-DS)The dominant driver gene is the GATA1 mutation. Additional frequently mutated genes include STAG2, RAD21, SMC1A, CTCF, EZH2, KANSL1, JAK3.11 In addition, constitutional trisomy 21 is present by definition in this disease.

Article Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
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2195971422009The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies.Korbel JO et al
3261389052015Transient myeloproliferative disorder with partial trisomy 21.Takahashi T et al
4223541712012Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.Malinge S et al
5223541662012DYRK1A in Down syndrome: an oncogene or tumor suppressor?Birger Y et al
6270310842016Low risk of solid tumors in persons with Down syndrome.Hasle H et al
7191766332009Malignancy in children with trisomy 21.Rabin KR et al
8194586182009Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.Baek KH et al
913783111992The role of angiogenesis in tumor growth.Folkman J et al
10178045202007Haematology of Down syndrome.Webb D et al
11344392982021The Mutational Landscape of Myeloid Leukaemia in Down Syndrome.de Castro CPM et al

Citation

Sheng Xiao, MD ; Chunxiao Yang

Pediatric Myeloid proliferation with Down syndrome

Atlas Genet Cytogenet Oncol Haematol. 2023-06-25

Online version: http://atlasgeneticsoncology.org/solid-tumor/209177/pediatric-myeloid-proliferation-with-down-syndrome