Hematopoietic stem ceils (HSCs) supply all blood cells throughout life by making use of their self-renewal and multilineage differentiation capabilities.HSC is commonly used for transplantation in patients with various hematologic malignancies as a rescue from high dose chemotherapy and radiation.The shortage of allogeneic stem cell donors and current inability to expand HSCs quickly and efficiently in vitro present challenges to developing successful cellular therapies.Recently, we have reported that human HSCs obtained from the mobilized peripheral blood and transduced with either SALL4A or SALL4B are capable of rapid and efficient expansion ex vivo by > 10,000-fold for both CD34+/CD38 and CD34+/CD38+ cells in the presence of appropriate cytokines.We demonstrated that these cells have retained their hematopoietic precursor cell immunophenotypes and morphology as well as their normal in vitro or in vivo potential for differentiation.Furthermore, the SALL4-mediated expansion was associated with enhanced stem cell engraftment and long-term repopulation capacity in NOD/SCID mice in vivo.Also, we demonstrated that the constitutive expression of SALL4 inhibited granulocytic differentiation and permitted expansion of undifferentiated cells in 32D myeloid progenitors.Finally, a TAT-SALL4B fusion gene was constructed and was shown to rapidly expand CD34+ cells.Our data provide a new avenue for investigating mechanisms of stem cell self-renewal, achieving clinically significant expansion of human HSCs and potentially help translate into feasible clinical trial studies.