The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in cytopenias and an increased risk of transformation to acute myeloid leukemia. Currently, the only curative therapy for MDS is an allogeneic hematopoietic stem cell transplantation (HSCT); however, old age and other comorbidities limit tolerability of conditioning regimens for HSCT, offsetting its benefits for patients. Among a wide range of genetic and epigenetic aberrations associated with MDS pathogenesis, dysregulation of ribosome biogenesis has been implicated. Using the Vav-cre-Asxl1-Tet2 mouse model of MDS, we show that delivering a ribosomal inactivating protein, saporin, via the internalization of the CD117 receptor, results in the depletion of normal and malignant stem cells with minimal effects on bone marrow cellularity. Furthermore, we show that the depletion of malignant cells allows for sufficient engraftment of healthy stem cells into recipient mice. Together, these studies demonstrate that CD117-saporin treatment leads to the depletion of malignant stem cells and can serve as a conditioning regimen for HSCT opening a potential therapeutic window for MDS treatment.