Understanding the mechanisms of normal and abnormal blood cell development
Mutations in transcription factors GATA1 and GATA2 are implicated in the development of blood disorders. We have an interest in understanding the role of these proteins in inherited anemias, leukemia, and myelodysplastic syndromes. Additionally, our laboratory explores the link between leukemia and Down syndrome. We use basic science to inform highly translational efforts. We strive to better understand disease progression and develop strategies for clinical intervention.
Focusing primarily on myeloid cells, the overarching focus of our laboratory centers on the mechanisms of normal and abnormal cell development. We study transcription factors and how they regulate specification or maintenance of particular lineages and focus primarily on the GATA1 and GATA2 transcription factors. In addition, we are investigating the signaling pathways and kinases that regulate differentiation of blood cells.
Our work in inherited hematologic disorders focuses on inherited anemias such as diamond blackfin anemia (DBA). Along this line of investigation, we are interested in how GATA1 mutations contribute to congenital anemias, with the goal of better understanding the disease and exploring the development of new treatments. Previous research in our laboratory has shown that the GATA1 short variant has an impaired ability to induce the activation of red cell or megakaryocyte genes. A major project in the laboratory aims to understand GATA1 partner proteins and to characterize the resultant protein complexes and transcription factors that are important for red cell and megakaryocyte production and maintenance. Although our research in the laboratory is rooted in basic science, it has translational implications, guiding therapeutic options for DBA and other inherited anemias that have GATA1 mutations.
In addition, our laboratory is launching a collaborative research project on a pediatric disease called GATA2 deficiency syndrome. The GATA2 mutations inherent in this syndrome lead to an immune disorder that has the propensity to later evolve into acute myelodysplastic syndrome or AML.
Children who have Down syndrome have a higher risk for developing B-cell acute lymphoblastic leukemia or a specific subtype of AML. Our laboratory investigates the role that genes on chromosome 21 play in the predisposition to those forms of leukemia. Evidence from our laboratory suggests that AML associated GATA1 mutations are acquired in fetal hematopoietic progenitor cells. A combination of these mutations and trisomy 21 leads to a disease called transient abnormal myelopoiesis (TAM), which has origins in utero and, for children with Down syndrome, comes with a higher risk of evolving into a form of AML called myeloid leukemia-Down syndrome (ML-DS). Our research aims to uncover how these GATA1 mutations contribute to ML-DS and which genes on chromosome 21 cause the predisposition for this form of leukemia. In addition, we strive to understand the genetic basis for the progression of TAM into ML-DS.
Along with developing a better understanding the mechanistic link between Down syndrome and leukemia, we are exploring the development of safer therapies for patients who tend to experience greater toxicities following conventional chemotherapy.
In our studies on malignant disorders, we are also investigating the progression of myelodysplastic and myeloproliferative neoplasms, both of which have a relatively high rate of transformation to acute myeloid leukemia. We study the biology of these diseases with a particular interest in how these diseases predispose people to subsequent AML, the type of which has no real treatment options. We aim to understand the pathways that drive myelodysplastic and myeloproliferative neoplasms progression to AML in order to development new treatments or find innovative strategies to stave off the onset of leukemia.
Dr. John D. Crispino joined St. Jude in 2020 as director of the Division of Experimental Hematology and holds the Wall Street Committee Endowed Chair. After earning his BA from Washington University and his PhD from the Massachusetts Institute of Technology, he completed a postdoctoral fellowship at Boston Children’s Hospital before launching his own innovative research program at the University of Chicago. He then moved his laboratory to Northwestern University, where he also earned his MBA. In addition to his leadership positions at St. Jude, Dr. Crispino has an active and flourishing research program that focuses on understanding the normal and malignant development of blood cells as well as exploring new treatment strategies for blood disorders.
Enthusiastic team of scientists committed to improving the lives of children with blood disorders