Developmental origins of leukemia in Down Syndrome
A third of babies with Down Syndrome are born with an abnormal blood production called TAM (transient abnormal myelopoiesis), which is an expansion of immature, leukemia-like, blood cells that carry a mutation called Gata1s. TAM is associated with a significant increase in death shortly after birth, and roughly 1 in 4 babies that survive the neonatal period develops leukemia before the age of 4. It is not well understood how or when TAM arises during fetal life. As a consequence, it is not possible to predict which infants with TAM will progress to acute leukemia, and importantly, there are no therapies that prevent the progression of TAM to cancer. We have found that we can model TAM in the laboratory using stem cells that are derived from patients that have both Down Syndrome and the Gata1s mutation. We hypothesize that TAM arises from the abnormal expression of GATA1s in a specific population of blood cell progenitors that arise in the early embryo and contain 3 copies of chromosome 21 (Down Syndrome). The evolution of TAM to leukemia requires the action of further mutations in genes that control DNA organization, including the CTCF and STAG2 genes. However, it is unclear how these mutations result in leukemia. We hypothesize that these mutant genes potentiate the action of GATA1s to drive the TAM cells to become fully malignant. We will use our patient-derived model to test these hypotheses, with the overall goal of understanding how to prevent TAM from progressing to leukemia.
Project Goals:
TAM (transient abnormal myelopoiesis) is common in babies with Down Syndrome and carries a significantly increased risk of death, as well as a high risk of progression to acute leukemia. The overall goal of this research project is to leverage the complementary expertise of Dr. Palis (Pediatric Oncology) in the development of the blood system and Dr. Steiner (Neonatology) in the regulation of genes found in blood cells to determine how TAM develops during fetal life and the mechanisms that allow it to ultimately evolve into acute leukemia. Babies with TAM have Down Syndrome (trisomy 21), as well a mutation in a gene important for blood development, called Gata1s. Our first goal is to better understand how GATA1s alters the identity of normal embryonic blood progenitor cells, in the setting of trisomy 21, to become TAM-like using stem cells that are derived from patients that have both Down Syndrome and the Gata1s mutation. Babies that progress to acute leukemia often acquire additional mutations in genes that are important for DNA organization (CTCF and STAG2), but it is not well understood why these mutations predispose to acute leukemia. Our second goal is to determine how the presence of mutations in the CTCF and STAG2 genes changes the function of GATA1s to drive TAM-like cells to become malignant. Our long-term goal is to develop novel therapies to treat Down Syndrome infants that are afflicted with TAM so that so that they do not develop leukemia.
Project Update 2024:
Infants with Trisomy 21 (Down’s Syndrome) commonly acquire mutations in the transcription factor GATA1, termed GATA1s, that leads to abnormal blood cell production and predisposition to the development of a unique form of myeloid leukemia during early childhood. We are using induced pluripotent stem cells to ethically model the early development of the human hematopoietic system. Using this model system we have demonstrated that in the context of Trisomy 21 (three copies of trisomy 21), the GATA1s mutation leads to the expansion of a fetal hematopoietic progenitor population called EMP, and also leads to a block in the development of erythroid lineage blood cells. We have further determined that in EMP with trisomy 21 GATA1s has different targets than the normal full length GATA1, particularly at pathways that regulate cell proliferation. Taken together, these data provide important insights in the mechanisms that underlie abnormal blood cell production in infants with Trisomy 21.
