Elke Will

HOXB4 Inhibits Cell Growth in a Dose-Dependent Manner and Sensitizes Cells Towards Extrinsic Cues

Ectopic expression of the homeodomain transcription factor HOXB4 expandshematopoietic stem and progenitor cells in vivo and in vitro, making HOXB4 a highlyinteresting candidate for therapeutic stem cell expansion. However, when expressedat high levels, HOXB4 concomitantly perturbs differentiation and thus likelypredisposes the manipulated cells for leukemogenesis. We therefore asked whetherthe expression level of HOXB4 may be a critical parameter that influences the growthand transformation properties of transduced cells. Using a set of retroviral vectorswhich covered a 40-fold range of expression levels, we studied the consequences ofHOXB4 expression at different levels in the well established Rat-1 fibroblast cellsystem. HOXB4 transformed Rat-1 fibroblasts beyond a certain threshold level ofexpression. Further escalation of HOXB4 expression, however, did not enhancetransformation. Nevertheless, HOXB4 mediated a dose dependent anti-proliferativeeffect on Rat-1 and NIH3T3 fibroblasts. This effect was aggravated under reducedserum concentrations and was, at least partially, due to an enhanced sensitivity ofHOXB4 overexpressing cells to induction of apoptosis. Based on these results wepropose that HOXB4 affects cell growth in a dose-dependent manner by sensitizingcells towards extrinsic signals.