Function of SATB1 as a critical regulator in acute myeloid leukemia
Final Report Abstract
Minimal reduction of the key hematopoietic transcription factor PU.1 in PU.1 UREΔ/+ mice induces a so called pre-cancerous or preleukemic state in the HSC compartment which is characterized by increased cycling and self-renewal of HSC, a phenotypical and functional myeloid bias. On molecular and phenotypical levels, these preleukemic stages closely resemble human myelodysplastic syndrome (MDS), which is often considered to be a pre-leukemic disease. In the background of deficient DNA mismatch repair, minimal PU.1 reduction is sufficient to trigger AML development, and UREΔ/+ Msh2-/- mice progress to disease in a stepwise manner. Animals develop disease with high phenotypic and morphologic heterogeneity, similarly to what is observed in human patients. Our data shows for the first time that PU.1 URE/Msh2 mice represent a very well characterized model to study and better understand the biology and progression of pre-leukemic stem cells and the underlying mechanisms of disease heterogeneity in AML. We could show that mutations in regulatory genomic regions, especially in transcription factor binding sites are able to alter the binding of transcription factors to their target regions and thereby change the expression profiles and fates of pre-leukemic and leukemic stem cells.
