The goal of this proposal is to elucidate the mechanisms by which loss of Runx1 in hematopoietic stem and progenitor cells alters their function, and contributes to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Inactivating mutations in RUNX1 are found in a high percentage of patients with AML of the least differentiated M0 subtype, and in MDS. MDS is a collection of blood disorders characterized by the inefficient production of one or more blood cell lineages, for which there is currently no cure aside from bone marrow transplantation. Loss of Runx1 in mice appears to recapitulate early stages of MDS, and is therefore a model for studying how impaired Runx1 function contributes to the development of this disease. We showed that loss of Runx1 causes hematopoietic stem cells and multipotent progenitors to proliferate more frequently, and that the expression of approximately 2000 genes and 40 microRNAs is altered in these populations. Here we propose to characterize the defects in HSCs and progenitors caused by Runx1 deficiency. We will examine whether genes whose expression is dysregulated in Runx1 deficient HSCs contribute to these defects. We will determine if treatment of mice with an agonist of a cytokine receptor that is under-expressed improves engraftment. Finally we will assess the contribution of several microRNAs to the engraftment defects associated with Runx1 deficiency, and their ability to cause MDS.
MDS is a disease associated with aging. The incidence of MDS is 0.7/100,000 during the fourth decade of live, and rises to 20.8 to 36.3/100,000 after the age 70 years. There are currently 35,000 to 55,000 MDS cases in the United States. Understanding the molecular basis of this disease may enable us to find new drug targets.
|Bellissimo, Dana C; Speck, Nancy A (2017) RUNX1 Mutations in Inherited and Sporadic Leukemia. Front Cell Dev Biol 5:111|
|Cai, Xiongwei; Gao, Long; Teng, Li et al. (2015) Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells. Cell Stem Cell 17:165-77|
|Satpathy, Ansuman T; Briseño, Carlos G; Cai, Xiongwei et al. (2014) Runx1 and Cbf? regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder. Blood 123:2968-77|
|Neel, Benjamin G; Speck, Nancy A (2012) Tyrosyl phosphorylation toggles a Runx1 switch. Genes Dev 26:1520-6|
|Cai, Xiongwei; Gaudet, Justin J; Mangan, James K et al. (2011) Runx1 loss minimally impacts long-term hematopoietic stem cells. PLoS One 6:e28430|
|Mangan, James K; Speck, Nancy A (2011) RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making. Crit Rev Oncog 16:77-91|