Here, we report that transcriptional repression mediated by N-CoR is essential for the suppression of growth and self-renewal potentials of HSCs and that loss of N-CoR function due to misfolding leads to ectopic reactivation of Flt3 and CD34-based hematopoietic stem cell phenotypes in promyelocytic and monocytic AML. This evidence concerns the gene FLT3 and acute myeloid leukemia.