Normal and Malignant Hematopoiesis
Center Leader: Carolyn Felix, MD
Gene and protein networks that signal blood cell maturation from primitive bone marrow progenitor cells, as well as networks that regulate the balance of cell growth and cell death, are especially relevant to hematopoiesis. Research at Children’s Hospital into this field focuses on networks that regulate the development of specific blood cell elements in normal and diseased states. The Normal and Malignant Hematopoeisis Research Affinity Group aims to address problems in these networks to develop targeted prevention and more effective treatments for disordered hematopoiesis, leukemia and lymphoproliferative diseases in children.
The progenitor cells in the hematopoietic system give rise to heterogeneous cell populations – red and white blood cells, as well as platelets – that execute specific functions. Technologies like gene expression profiling and proteomics have revealed global pictures of the networks that distinguish specific blood cell elements in normal and malignant states. Current research in the affinity group involves deciphering which elements in these networks can be targeted for new treatments and, ultimately, for preventing diseases of the hematopoietic system.
The Normal and Malignant Hematopoeisis Research Affinity Group brings together investigators engaged in clinical, translational and basic research who are skilled in oncology, hematology, stem cell transplantation, cytogenetics, biochemistry, epidemiology, pharmacology, pathology, immunology, cell biology and bioinformatics. Linking new technologies and knowledge integration hold promise for better diagnosing, treating and preventing pediatric diseases of the hematopoietic system.
Recent hematopoesis research at Children’s Hospital is focused on leukemia, the most common childhood cancer, and its two major subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Whereas most children diagnosed with ALL can be cured, the prognosis remains poor for the 20 percent of patients diagnosed with AML.
Hospital researchers are focused on synergistic studies with the long-term goal of developing preventative strategies and leukemia-specific treatments for various forms of pediatric AML. A form of AML, which occurs as a complication of anticancer chemotherapy, has an especially poor prognosis. One project examines how disruption of the cellular protein called topoisomerase II causes chromosomal breakage that leads to AML. A mechanistic understanding of the cause of this form of AML could lead to safer chemotherapy regimens and protective compounds.
Another focus of hematopoesis research in the affinity group is GATA-1, a critical transcription factor protein that programs the expression of genes in blood cell development. Patients with Down syndrome are especially susceptible to AML, and the GATA-1 transcription factors is abnormal in the form of AML associated with Down syndrome.
Investigators in this affinity group are also pursuing a strategy to reduce the complications and mortality from infections associated with intensive AML treatment regimens by determining individual genetic variations that underlie infection risk.
Other affinity group research is focused on dissecting signaling pathways in immune cells called NKT cells to determine their role in the immune response, which may prove relevant to the development of immunity against tumors.
These interdisciplinary projects ultimately have potential to advance the current knowledge on normal and malignant hematopoiesis as well as to translate knowledge on the science of hematopoiesis to reduce morbidity and mortality in heterogeneous forms of leukemia in children.
Activities of the research affinity group, including a rich seminar series and annual retreat, facilitate the progress of an ever-expanding web of researchers with a common interest in broad areas of hematopoiesis within the Stokes Institute, the Children’s Hospital campus and beyond. This avenue to combining expertise in specific areas from new interchanges beyond the clinic and the individual laboratory will speed the Hospital’s advances in promoting bench-to-bedside research.