Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and invivo

Several studies point to multiple members of the Hox transcription factor f amily as playing key roles in normal hematopoietic development, and they li nk the imbalanced expression of these transcription factors, in particular of the Abd-like A cluster HOX genes HOXA9 and HOXA10 to leukemogenesis. To test directly the hypothesis that HOXA10 is involved in human hematopoletic development, the gene was retrovirally overexpressed in human highly purif ied CD34(+)/GFP(+) hematopoietic progenitor cells derived from cord blood o r fetal liver sources, and the impact of aberrant gene expression was analy zed on differentiation and proliferation in vitro and in vivo. HOXA10 misex pression profoundly impaired myeloid differentiation with a higher yield of blast cells in liquid culture and a greater than 100-fold increased genera tion of blast colonies after in vitro expansion or after replating of prima ry colonies first plated in methylcellulose directly after transduction (P< .01). Furthermore, aberrant HOXA10 expression almost completely blocked ery throid differentiation in methylcellulose (P<.02). HOXA10 deregulation also severely perturbed the differentiation of human progenitors in vivo, reduc ing B-cell development by 70% in repopulated NOD/SCID mice and enhancing my elopoiesis in the transduced compartment. The data provide evidence that th e balanced expression of HOXA10 is pivotal for normal human hematopoietic d evelopment and that aberrant expression of the gene contributes to impaired differentiation and increased proliferation of human hematopoietic progeni tor cells. These results also provide a framework to initiate more detailed analyses of HOX regulatory domains and HOX cofactors in the human system i n vitro and in vivo.(Blood. 2001;97:2286-2292) (C) 2001 by The American Soc iety of Hematology.