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A critical factor in blood (hematopoietic) stem and progenitor cell (HSPC) gene modification remains the effective delivery of the needed gene to long-term repopulating stem cells – the very cells that are stem cells which can give rise to all cells in the body. For viral gene therapy, that is using a virus to deliver genes or to modify genes, the delivery must be efficient and safe. Our group has helped to pioneer Lentiviral Vector gene delivery strategies for blood stem and immune B cells in a research setting. We have found conditions that minimizes cell treatment time and maximizes the number of cells targeted by Lentiviral Vectors. These procedural improvements may be of importance for advancing the fields of gene therapy for the clinical purposes. Our current studies are focused on the identification of small molecules and changes in Lentiviral Vectors that improve and make more safe gene delivery to blood stem and B cells. Lastly, unraveling the mechanisms whereby blood cells restrict viral entry and regulate cellular responses will allow this “cellular restriction code” to be translated and applied to viral vectors and nanoparticles to transport gene payloads to desired cell populations for gene correction of human diseases. Our group has a longstanding interest in the regulation of myeloid development and function by the transcription factor SPI1 (PU.1). We have recently uncovered and reported that SPI1 regulates the expression of the predominately myeloid specific Hexokinase 3 protein. In contrast, Hexokinase 1 and 2 are broadly expressed in many cells in the body. The hexokinases family catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. In contrast to the role of Hexokinase 2 regulating energy metabolism in macrophages and neutrophils, we have found that Hexokinase 3 does not appear to have an analogous role in myeloid cells but appears to promote survival of acute myeloid leukemia cancer cells and possibly normal myeloid cells. Studies are underway to better understand the role of the myeloid predominate Hexokinase 3 in healthy myeloid cells and myeloid cancer cells in people.