While people with Down syndrome are typically recognized by certain physical features, they are also a higher risk group for a number of diseases and disorders. One example is transient abnormal myelopoiesis, or TAM, a preleukemic disorder. CiRA Associate Professor and pediatrician Megumu Saito and his research team use iPS cells from a Down syndrome patient to explore the causes of TAM, identifying a specific subpopulation of cells that seems particularly vulnerable to this disease.

While Down syndrome is well known for its effects on intelligence, people with Down syndrome are also more likely to develop serious diseases, such as leukemia and TAM.

More than 95% of Down syndrome cases are the result of trisomy 21, in which there are three copies of chromosome 21 rather than the normal two. For TAM, however, a mutation in the GATA1 gene, which is known to have a vital role in blood development, is also required.

In classical hematopoiesis, all types of blood cells, such as erythrocytes, megakaryocytes, and myeloid cells, are derived from a common stem cell. As hematopoiesis proceeds, the common stem cell breaks off into different cell subpopulations.

"We do not know which cell subpopulation is most affected by the GATA1 mutation. This subpopulation would make a good target for treatments," explains Saito.

The researchers used iPS cells made from a Down syndrome patient with TAM to explore how normal blood development is disturbed by the combination of trisomy 21 and the GATA1 mutation.

By gene editing, they corrected the GATA1 mutation in some iPS cells to compare blood development in trisomy 21 cases with and without the mutation. They found three subpopulations that behaved differently between the mutant and unmutated conditions.

"We divided the subpopulations based on their marker expressions for myeloid cells, erythroid and megakaryocytic progenitors. The data suggested that the mutation caused more myeloid lineages and immature megakaryocytic lineages," explained pediatrician Dr. Akira Niwa, who was one of the authors of the study.

Further experiments found the genes responsible for differentiation to erythroid and mekaryocytic cell types in the mutant subpopulations were relatively dormant. At the same time, the mutant subpopulations produced more myeloid cells.

"We observed an explosion of myeloid cell proliferation and deficient erythrocyte differentiation and megakaryoblast maturation in the mutant group," explains Dr. Yoko Nishinaka-Arai, another author of the study.

TAM appears in infancy, and in the majority of cases, TAM will naturally resolve itself. For patients not so fortunate, however, TAM could be the beginnings of leukemia before one's fifth birthday.

"Our model is not only to study TAM, but to predict and prevent the leukemia that is commonly seen afterwards," says Saito.

• doi: 10.3324/haematol.2019.242693