Myelodysplastic syndromes (MDS) are clonal stem cell diseases characterized mainly by ineffective hematopoiesis. Here, we present an approach that enables robust long-term engraftment of primary MDS stem cells (MDS-SC) in mice by implantation of human mesenchymal cell-seeded scaffolds. Critically for modeling MDS, where patient sample material is limiting, mononuclear bone marrow cells containing as few as 104 CD34+ cells can be engrafted and expanded by this approach with the maintenance of the genetic make-up seen in the patients. Noninvasive high-resolution ultrasound imaging shows that these scaffolds are fully perfused. Our data show that the human microenvironment but not mouse is essential to MDS-SC homing and engraftment. Notably, the alternative niche provided by healthy donor mesenchymal stromal cells enhances engraftment of MDS-SCs. This study characterizes a new tool to model MDS human disease with the level of engraftment previously unattainable in mice and offers insights into human-specific determinants of the MDS-SC microenvironment. SIGNIFICANCE: These findings are significant for understanding the niche dependence of MDS. This report provides the evidence of the migratory behavior of hematopoietic stem cells in myeloid cancers. Our model offers a unique opportunity to study the clonal behavior of the myeloid/lymphoid cancers and delineate how cancer cells interact with different niches.