Leukemogenic Transformation by Anterior HOXA-Cluster Genes.

Abstract 2962

Poster Board II-938

HOX homeobox genes are important regulators of normal and malignant hematopoiesis and abdominal-type HOXA-cluster genes, in particular HOXA7 to HOXA10, are highly leukemogenic. However, little is known about the transforming abilities of anterior HOXA genes HOXA1 to HOXA6 despite a high prevalence of anterior HOX-expression in acute leukemia. Here we performed a comprehensive assessment of the oncogenic potential of every HOXA gene in primary hematopoietic cells. With exception of HOXA2 and HOXA5 all other HOXA genes caused a block or delay of hematopoietic differentiation in serial replating assays and all HOX genes also cooperated with Meis1. No evidence for the alleged tumor-suppressor function of HOXA5 could be found. Whereas all other active HOXA genes induced the outgrowth of mixed granulocytic/monocytic cells, HOXA13 preferentially specified the development of monocytes/macrophages. Albeit more weakly than HOXA9 also the anterior HOXA genes HOXA1, HOXA4, and HOXA6 transformed cells and generated permanent myelomonocytic cell lines arrested at various stages of differentiation. HOX-RNA profiling revealed that each of these lines also transcribed HOXA9. However, kinetic studies with inducible HOX-derivatives showed that HOXA9 expression was not under control by anterior HOXA proteins. Cellular differentiation was induced immediately after loss of anterior HOX activity and HOXA9 down regulation was a secondary event during maturation. This proves that anterior HOX proteins are able to transform hematopoetic cells through an individual contribution independent of HOXA9. In summary our results explain how HOXA9 can predominate in hematologic malignancies while simultaneously it is not necessarily required for transformation.