Controlled stem cell amplification by HOXB4 depends on its unique proline-rich region near the N terminus

There is high interest in understanding the mechanisms that drive self-renewal of stem cells. HOXB4 is one of the few transcription factors that can amplify long-term repopulating hematopoietic stem cells in a controlled way. Here we show in mice that this characteristic of HOXB4 depends on a proline-rich sequence near the N terminus, which is unique among HOX genes and highly conserved in higher mammals. Deletion of this domain substantially enhanced the oncogenicity of HOXB4, inducing acute leukemia in mice. Conversely, insertion of the domain into Hoxa9 impaired leukemogenicity of this homeobox gene. These results indicate that proline-rich stretches attenuate the potential of stem cell active homeobox genes to acquire oncogenic properties. •The conserved proline-rich region is essential for HOXB4 to amplify long-term hematopoietic stem cells without loss of homeostasis.•Loss of this region increases leukemogenicity of HOXB4, altering its DNA-binding properties.