epigenetic regulation of haematopoietic stem cell differentiation and tumourigenesis

in recent years, epigenetic events have been shown to play a central role in cell fate decisions and have been implicated in both normal differentiation and in oncogenic transformation. there is substantial evidence that haematopoietic stem cells are the target for leukemic transformation in acute myeloid leukaemia (aml) and in certain acute lymphoid leukaemias (all). with age, there is a decrease in the lymphoid potential of haematopoietic stem cells- this is paralleled by a decreased incidence of lymphoid leukemias and an increase in myeloid malignancies. the aim of this collaborative study is to compare the chromatin structure of lymphoid- and myeloid-affiliated genes in leukemic initiating cells from aml patients with that of haematopoietic stem cells from age-matched control subjects. the group of janusz siedlecki (warsaw) will study dna methylation and that of michele goodhardt (paris) will determine the histone modification profile of normal and leukemic stem cells. these studies should determine whether leukemic transformation or aging of haematopoietic stem cells are associated with epigenetic silencing of lymphoid genes. to further investigate whether intrinsic changes in haematopoietic stem cells underlie the increased incidence of myeloproliferative diseases with age, we will transduce haematopoietic stem cells from young and old individuals with the mll-enl oncogene and determine whether aging alters the leukemogenic potential of mll fusion proteins and their profile of target genes. the study of epigenetic modifications associated with aging and leukemic transformation of haematopoietic stem cells should contribute to our understanding of the biology and ultimately the clinical treatment of these leukemias. the identification of genes associated with aberrant dna methylation or histone modifications can be used as biomarkers for malignant stem cells and indicators of response to therapy. since epigenetic-based mechanisms are reversible and can be modified by pharmacological intervention, our study of the chromatin structure of primitive transformed cells could contribute to the development of new tools for targeted therapy of leukemic patients.