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

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