(A) Characterization of the stem/progenitor cell compartment of Lsd1 knockout mice demonstrated the presence LT-HSCs (CD150+ CD48− LSK), while having lost all LS−K+ myeloid progenitor cells (i.e., CMP, GMP, and MEP) in the bone marrow. In line with this, Lsd1-deficient bone marrow cells could not contribute to multilineage hematopoiesis in competitive transplantation assays. Accordingly, Lsd1-deficient HSCs maintained an immature cellular morphology, an LS+K+ immunophenotype, and were incapable of giving rise to mature cells, in colony formation cell assays, which we used to directly test LT-HSC differentiation capability. Gene expression profiling of Lsd1-deficient CD150+ CD48− LSK cells demonstrated upregulation of hematopoietic stem and progenitor cell signature genes. Collectively, our data suggested that the inability to silence HSPC genes keeps Lsd1 knockout LT-HSCs from differentiating into myeloid progenitor cells and lineage commitment. (B) Lsd1 deficiency in granulocytic and erythroid cells resulted in erroneous derepression of stem and progenitor cell gene sets, which resulted in stark maturation defects in the mature erythroid and granulocytic cell lineages. These findings suggested that Lsd1 is required to maintain appropriate expression levels of HSPC genes during early, as well as late hematopoietic differentiation and that the failure to so, is incompatible with terminal differentiation.