GSE117060
The homeobox transcription factor HB9 induces senescence and blocks differentiation in hematopoietic stem and progenitor cells
The translocation t(7;12)(q36;p13) occurs in infants and very young children with AML and usually has a fatal prognosis. Whereas the transcription factor ETV6, located at chromosome 12p13, has largely been studied in different leukemia types, the influence of the translocation partner HB9 (chr. 7q36), is still unknown. This is particularly surprising as ectopic expression of HB9 is the only recurrent molecular hallmark of translocation t(7;12) AML. We investigated the influence of HB9 as a potential oncogene on cell proliferation and cell cycle in vitro, as well as on hematopoietic stem cell differentiation in vivo using murine and human model systems.   We show, that HB9 induces premature senescence in human HT1080 and murine NIH3T3 cells, providing for the first time evidence for an oncogenic potential of HB9. Furthermore, HB9-transduced primary murine hematopoietic stem and progenitor cells underwent a profound differentiation arrest and accumulated at the megakaryocyte/erythrocyte progenitor stage, resulting in a premalignant myeloid cell population in vivo. Concomitantly, HB9 expression upregulates erythropoiesis-related genes in primary human hematopoietic stem and progenitor cells, and enriches gene expression profiles for cell cycle and mitosis-related biological processes.   In summary, the novel findings of HB9 dependent premature senescence and perturbed hematopoietic differentiation shed light on the oncogenic properties of HB9 in translocation t(7;12) AML and offer novel targets for therapeutic intervention. Overall design: CD34+ cells were transduced with either GFP or HB9