Infants and children with trisomy 21 (Down syndrome) often have numerous blood disorders. These can include anemia and thrombocytopenia, as well as a predisposition to two related leukemias: transient myeloproliferative disease (TMD) and acute megakaryoblastic leukemia (AMKL).
Research conducted at CHOP’s Center for Childhood Cancer Research (CCCR) and elsewhere are focused on how an extra copy of chromosome 21 and mutations in a gene (GATA1) that controls normal blood cell development predispose children with Down syndrome to blood diseases including two related leukemias: transient myeloproliferative disease (TMD) and acute megakaryoblastic leukemia (AMKL).
A major problem that impedes a better understanding of how Down syndrome and mutations in the GATA1 gene affect normal blood cell development is that existing mouse models of Down syndrome do not fully recapitulate the hematologic abnormalities exhibited with the disease. To overcome this problem, researchers at the CCCR, including Stella T. Chou, MD, are focusing on the use of primary patient samples and creation of induced pluripotent stem cells (iPSCs) from children with Down syndrome.
CHOP’s Center for Childhood Cancer Research is one of the few places in the world that is using primary cell systems to study the effects of Down syndrome on normal and malignant hematopoietic development.
Research using iPSCs created from Down syndrome patients with TMD as well as non-Down syndrome patients with a congenital anemia revealed that GATA mutations result in defective erythropoiesis but enhanced megakaryocytic proliferation. Primary cells and iPSCs derived from Down syndrome patients have been used to show that normal blood cell development is altered in the context of trisomy 21 and that a single extra copy of chromosome 21 can alter hematopoietic gene expression and increase megakaryocyte progenitor proliferation.
An additional area of research focus is to use DNA-based analyses to prevent Rh alloimmunization following blood transfusion in children with sickle cell disease. These patients frequently inherit RH variants and form anti-Rh antibodies, complicating transfusion therapy.