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ASH-EHA Joint Symposium Dives Deep Into the Leukemia–Down Syndrome Connection


While several associations between constitutional syndromes, such as Down syndrome, and predisposition to cancers have been recognized, recommendations for surveillance or clear association between the 2 are lacking.

While several associations between constitutional syndromes, such as Down syndrome, and predisposition to cancers have been recognized, recommendations for surveillance or clear association between the 2 are lacking. Speakers at a joint symposium between the American Society of Hematology (ASH) and The European Hematology Association, held on the second day of the 60th ASH Annual Meeting & Exposition, being held December 1-4, in San Diego, California, highlighted the current understanding of cancer surveillance screening, as well as translational studies that target pathways in these and related hematologic malignancies.

Between 5% and 30% of children with Down syndrome are born with transient leukemia of Down syndrome (TL-DS), also called transient myeloproliferative disorder.1 Mutations in the transcription factor gene GATA1, in conjunction with trisomy 21 (T21), are key drivers of this myeloproliferative disorder. Research has shown that TL-DS may lead to early death in 15% to 23% of cases; survivors may develop acute myeloid leukemia (AML) of Down syndrome in the first 4 years of their life.

While guidelines for management of TL-DS have recently been developed in the United Kingdom,2 a lot remains to be discovered.

The first presentation during the joint session, "Leukemia in Down Syndrome: Why Does It Happen and Why Is It Important?" was by Irene Roberts, MD, MRC Molecular Haematology Unit and Paediatrics, MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom.

There is increased susceptibility to leukemia in Down syndrome, both myeloid and lymphoid leukemias are common, and young children are especially susceptible, Roberts said. “The incidence ratio for AML is 12 in adults and 114 in children. On the other hand, the incidence of acute lymphoblastic leukemia is 13 in adults and 27 in children less than 4 years of age,” Roberts told the audience. The incidence is negligible in solid tumors.

For her talk, Roberts focused on AML.

Myeloid leukemia of Down syndrome (ML-DS) originates in fetal life and presents before the child is 4 years of age. “It is preceded by a stage called transient abnormal myelopoiesis or TAM,” Roberts explained. Development of TAM and ML-DS both require trisomy 21 and acquired GATA1 mutations.

Neonatal preleukemia, she said, results from the N-terminal truncation of GATA1 protein, called GATA1s, in T21 cells. Additional mutations cause ML-DS in persisting mutant GATA1 cells and results in ML-DS before age 4.

What is the importance and relevance of leukemia in DS?

Roberts listed several characteristics of this phenomenon based on what is known in the literature, combined with her laboratory’s findings:

  • It provides a model of the natural history of leukemia within a defined time window
  • It provides insight into GATA1 function
  • T21 leads to adapting to aneuploidy, gene dosage, tT21 in non-DS leukemias
  • Managing constitutional syndromes with malignant potential to implement research findings in the clinic
  • Beyond the leukemia itself, there are policy and societal issues associated with this phenomenon.

Neonates with higher blasts and clinical TAM had more severe disease, as determined by using hepatomegaly, effusions, and splenomegaly. Disease severity was determined based on infiltration of tissue into mutant blast cells and fibrosis.

Roberts said that GATA1 mutations in DS neonates predict for translation of GATA1s, which is the N-terminal truncated protein. It can lead to abnormal platelet production in DS neonates. Another characteristic of TAM is giant platelets and megakaryocyte fragments.

A significant finding is that GATA1 mutations are likely acquired late in the second trimester or early in the third trimester of fetal development. The progression of TAM to ML-DS has several driver mutations, but 2 most frequent mutations are in Cohesin and CTCF.

Roberts summed her findings by delineating clinical implications of the leukemia-DS relation. “Children at high risk of developing myeloid leukemia within 4 years can be identified at birth based on the percentage of blasts and also by GATA1 mutation analysis,” she said. This would also provide insight into those children who are at a low or no risk of developing myeloid leukemia based on their blast count.

“A close liaison among hematologists, pediatricians, and neonatologists for guideline development would be important,” which she highlighted has recently been done in the United Kingdom.2

Presenting the developments in the United States was John D. Crispino, PhD, MBA, Division of Hematology and Oncology, Northwestern University, Chicago, Illinois.

GATA1, a zinc finger-binding transcription factor, is important for megakaryopoiesis, Crispino said, with N-terminal mutants leading to congenital dyserythropoietic anemia, congenital thrombocytopenia, and congenital erythropoietic porphyria. The GATA1s mutation can result in transient abnormal myelopoiesis, ML-DS, congenital hypoplastic anemia, and Diamond Blackfan Anemia.

The importance of GATA1 in erythropoiesis is underscored by the fact that GATA1-deficient mice die of anemia, Crispino said.

Crispino’s laboratory conducted high-throughput studies in vitro to identify small molecule drugs that could target the GATA1 deficiency in cells and to query if these drugs had disease-altering activity. Subsequent studies evaluated small-molecule drugs that could force polyploidization in megakaryocytes and their maturation. This eventually led to the identification of Aurora kinase—which regulates cell cycle and proliferation—as a potential target, inhibition of which can induce polyploidy and differentiation in megakaryocytic leukemia cells. Additionally, “the Aurora kinase inhibitor, alisertib, also caused a delayed differentiation-associated apoptosis,” Crispino said.

In mouse studies, primary human megakaryocyte leukemia cells in mice, which were then treated with 2 cycles of alisertib and bone marrow was assayed at 27 days. The drug reduced immature human megakaryocytes in the mice and upregulated the mature megakaryocytes. The study also found a survival effect of alisertib.

Crispino’s group then treated a myeloproliferative neoplasms-AML cell line with alisertib and found that it increased both polyploidization and GATA1 protein expression.

When mice injected with these cells were injected with 3 cycles of alisertib, the infiltrated mice had a high platelet count and transient increase in hemoglobin and hematocrit.

Since these studies identified Aurora kinase A as a therapeutic target in myelofibrosis, further studies are now evaluating the drug in the clinic.

“Can this strategy be used in the treatment of other GATA1 deficiency syndromes?” Crispino asked. This question remains unanswered.


  1. Roberts I, Alford K, Hall G, Juban G, 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(24):3908-3917. doi: 10.1182/blood-2013-07-515148.
  2. Tunstall O, Bhatnagar N, James B; British Society for Haematology. Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome. Br J Haematol. 2018 Jul;182(2):200-211. doi: 10.1111/bjh.15390.
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