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

• Published in: Blood 2000-12, Vol.96 (12), p.3887-3893
• Main Authors: DiMartino, Jorge F., Miller, Trissa, Ayton, Paul M., Landewe, Theresa, Hess, Jay L., Cleary, Michael L., Shilatifard, Ali
• Format: Article
• Language: English
• Subjects: Acute Disease; Amino Acid Sequence; Animals; Biological and medical sciences; Bone Marrow Cells; Cell Nucleus - chemistry; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - pharmacology; Embryo, Mammalian - cytology; Fibroblasts - cytology; Hematologic and hematopoietic diseases; Histone-Lysine N-Methyltransferase; Interleukin-3 - pharmacology; Leukemia, Myeloid - etiology; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myeloid Progenitor Cells - chemistry; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - drug effects; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - pharmacology; Peptide Elongation Factors - genetics; Peptide Elongation Factors - pharmacology; Protein Structure, Tertiary; Proto-Oncogenes; RNA Polymerase II - metabolism; Structure-Activity Relationship; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - pharmacology; Transcription, Genetic - drug effects; Transcriptional Elongation Factors; Transfection; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.12.3887

The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid leukemias 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 transcriptional elongation activity of ELL but relocalizes it from a diffuse nuclear distribution to the nuclear bodies characteristic of MLL. Using a serial replating assay, it was demonstrated that the MLL-ELL chimeric protein is capable of immortalizing clonogenic myeloid progenitors in vitro after its 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 activity 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-ELL in a transient transcriptional assay. These data indicate that neoplastic transformation by the MLL-ELL fusion protein is likely to result from aberrant transcriptional activation of MLLtarget genes. Thus, in spite of the extensive diversity of MLL fusion partners, these data, in conjunction with previous studies of MLL-ENL, suggest that conversion of MLL to a constitutive transcriptional activator may be a general model for its oncogenic conversion in myeloid leukemias.