Finding new genes critical for blood production
The human bone marrow is the pivotal organ in the replacement of the vast numbers of blood cells normally consumed each day. One of the cells regenerated by this organ are the red blood cells which are critical for the transport of oxygen to the tissues. This project uses genetically altered mice to identify genes that are critical for the production of normal red blood cells. The results of these studies will provide insights into a variety of human conditions, including anemia.
Selected Publication: Rank G, Sutton R, Marshall V, Lundie RJ, Caddy J, Romeo T, Fernandez K, McCormack MP, Cooke BM, Foote SJ, Crabb BS, Curtis DJ, Hilton DJ, Kile BT and Jane SM. Novel roles for erythroid Ankyrin-1 revealed through an ENU-induced null mouse mutant. Blood 113: 3352-3362, 2009.
Regulation of the human hemoglobin genes
Hemoglobin is the major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production are the commonest genetic diseases world-wide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, fetal hemoglobin. We have identified key factors important for fetal gene expression. Our goal is to translate these findings into therapies for the hemoglobin disorders.
Selected Publication: Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD, Cunningham JM and Jane SM. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A coupling histone and DNA methylation in gene silencing. Nature Structural Cell Biology 16: 304-311, 2009.
Finding cures for myelodysplasia
Myelodysplastic syndrome is a preleukemic condition which is poorly understood and occurring at an increasing frequency. Unfortunately no targeted therapy exists. Two features of the disease are abnormal gene expression and abnormal cell death. We have a uniquely accurate model of this disease, and we plan to use it to investigate these two phenomena. The findings of this project will lead to greater understanding of the disease and new molecular targets for therapeutic agents to be developed and tested in our model.
Selected Publications: Slape C, Lin YW, Hartung H, Zhang Z, Wolff L and Aplan PD. NUP98-HOX translocations lead to myelodysplastic syndrome in mice and men. J Natl Cancer Inst Monogr 39: 64-68, 2008.
Slape C*, Liu LY*, Beachy S and Aplan PD. Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras and Cbl. Blood 112(5): 2017-2019, 2008.
The role of thymic self renewal in causing T-cell Acute Lymphoblastic Leukaemia
White blood cells known as T-cells play a key role in protecting our body against infection and disease. However in cancers such as T-cell Acute Lymphoblastic Leukaemia (T-ALL), the build-up of ‘damaged’ T-cells can lead to death. Researchers in this project recently discovered that the gene Lmo2, which can cause T-ALL to develop, also gives stem-cell like properties to T-cells. Lmo2 also allows T-cells to self-renew. This stem cell-like property allows these cells to persist in the thymus for years, unlike normal thymus cells which remain only for a couple of weeks. This longevity appears to allow the T-cells time to accumulate the additional mutations required for leukaemia to develop. We are investigating how Lmo2 activates the self-renewal process in T-cells and hope to be able to determine whether we can disrupt self-renewal of thymus cells and prevent or treat T-cell leukaemia. These studies may also provide new targets for T-ALL therapy.