Proline Rich Homeodomain (PRH/HHEX) protein in the control of haematopoiesis and myeloid cell proliferation and its potential as a therapeutic target in myeloid leukaemias and other cancers: PRH in myeloid cells

Myelopoiesis occurs as a consequence of the interplay between transcription factors and growth factor dependent signalling pathways impacting on cell proliferation, cell survival and cell differentiation. It is equally well established that mis-regulation of transcription factors and/or growth factor receptor pathways contributes to disruption of myelopoeisis and the genesis of chronic and acute myeloid leukaemias. The Proline Rich Homeodomain protein (PRH, also known as HHEX) is a transcription factor that binds to DNA using a conserved motif known as the homeodomain and regulates the expression of multiple genes involved in cell growth control. In addition PRH has the ability to repress growth control genes post-transcriptionally via the regulation of mRNA transport. PRH is essential for haematopoiesis and this protein is expressed in haematopoietic stem cells and all myeloid lineages. PRH also plays a role in early embryonic development and in the formation of many organ systems. Significantly, there is compelling evidence that PRH is mis-regulated in both chronic myeloid leukaemia and some subtypes of acute myeloid leukaemia as well as in T- cell leukaemias and some solid cancers. This chapter reviews the functions of PRH in normal haematopoiesis and in myeloid leukaemias and focuses on the structure, localisation, transcriptional activity and post-translational modifications of PRH. In myeloid cells, PRH has been shown to be a transcriptional repressor of genes that regulate cell proliferation/survival including multiple genes in the VEGF signalling pathway. Thus PRH is a potent inhibitor of myeloid cell proliferation. Protein kinase CK2 is a stress responsive kinase with pleiotropic activities that promotes cell proliferation and its activity is often elevated in leukaemia and solid tumours. Phosphorylation of PRH by CK2 inhibits DNA binding by PRH and alleviates growth inhibition by PRH. Therapeutic treatment for CML (imatinib and dasatinib) also influences PRH phosphorylation and increases transcriptional repression of growth regulatory genes by PRH. Here we review the evidence which suggests that PRH
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may be an important therapeutic target in CML and other leukaemias, as well as in other cancers.