A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL.

摘要: The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid leukemias fuses the gene encoding transcriptional elongation factor ELL to MLL with consequent expression of an MLL-ELL chimeric protein. To identify potential mechanisms leukemogenesis by MLL-ELL, its and oncogenic properties were investigated. Fusion preserves activity but relocalizes it from a diffuse nuclear distribution bodies characteristic MLL. Using serial replating assay, was demonstrated that protein is capable immortalizing clonogenic progenitors vitro after retroviral transduction into primary murine hematopoietic cells. However, structure–function analysis indicates domain not essential for transformation because mutants lacking retain potent ability immortalize progenitors. Rather, highly conserved carboxyl terminal R4 both necessary sufficient contribution associated MLL-ELL. demonstrates activation required transactivation HoxA7 promoter transient assay. These data indicate neoplastic fusion likely result aberrant target genes. Thus, spite extensive diversity partners, these data, conjunction previous studies MLL-ENL, suggest conversion constitutive activator may be general model leukemias.