The role of HOXB4 in myelofibrosis and new therapy targeting USF

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We examined the gene expression patterns of Lineage-Sca1+ BM cells in JAK2V617F transgenic mice that developed myelofibrosis, and found that HOXB4 and TGF-b1, the target genes of transcriptional factor USF1, were highly expressed. The transcriptional activity of USF1 is up-regulated by thrombopoietin stimulation or JAK2 V617F via activation of MAPK.Somatic loss-of-function mutations of TET2 are frequently observed in patients with myeloproliferative neoplasams. Mice with low TET2 exhibited only mild monocytosis, splenomegaly, and extramedullary hematopoiesis compared to wild type mice. HSCs from TET2 low mice exhibit increased self-renewal ability in vivo. In competitive transplantation assays, HSCs from TET2 low mice possess a competitive growth advantage over wild type HSCs. These data indicate that TET2 plays a critical role in HSC homeostasis.