Enhanced in vivo regenerative potential of HOXB4-transduced hematopoietic stem cells with regulation of their pool size

After bone marrow transplantation (BMT), there is a rapid regeneration to n ormal pretransplantation levels in the number of hematopoietic progenitors and mature end cells, whereas hematopoietic stem cell (HSC) numbers recover to only 5% to 10% of normal levels. This suggests that HSC are significant ly restricted in their self-renewal behavior and hence in their ability to repopulate the host stem cell compartment. Previously, we have reported tha t HSC engineered to overexpress the homeobox transcription factor HOXB4 hav e a large repopulation advantage over untransduced cells as assessed at 4 m onths in a murine transplantation model (Sauvageau et al, Genes Dev 9:1753, 1995). This phenomenon has now been examined in detail for periods extendi ng to 12 months in cohorts of mice transplanted with various numbers of HOX B4-transduced HSC, In all mice analyzed, HOXB4-transduced HSC were capable of fully reconstituting the HSC compartment, resulting, on average, in some 14-fold greater numbers of HSC than observed when transplanting control, n on-HOXB4-transduced bone marrow cells. These data indicate that HOXB4 is a limiting factor in the regeneration of HSC to normal levels after BMT Furth ermore, we show that HOXB4-transduced HSC did not expand above levels norma lly observed in unmanipulated mice, indicating that its overexpression does not override the regulatory mechanisms that maintain the HSC pool size wit hin normal limits. (C) 1999 by The American Society of Hematology.