The FEL (AF-4) protein donates transcriptional activation sequences to Hrx-Fel fusion proteins in leukemias containing T(4;11)(Q21;Q23) chromosomal translocations.
The t(4;11) chromosomal translocation marks a subset of acute lymphoblastic and secondary myeloid leukemias. It results in the fusion of the FEL (AF-4) gene on chromosome band 4q21 with the HRX (MLL) gene on chromosome band 11q23. This translocation results in the expression of fusion transcripts from both translocated chromosomes, with the derivative 11 product (fusing the amino-terminal third of the Hrx protein to the C-terminal two-thirds of the Fel protein) thought to be involved in leukemic transformation. The mechanism of transformation by Hrx-Fel in leukemic cells, however, is unknown and the specific leukemogenic contributions of Fel have not been defined. In this study, we demonstrate that Fel is capable of activating transcription from a minimal adenoviral E1b promoter as a Gal4-Fel fusion protein in transient transcriptional assays. The Fel transactivating sequences were localized to amino acids 365-572 which are consistently retained by Hrx-Fel fusion proteins created by t(4;11) translocations in leukemias. Furthermore, we demonstrate that the transactivation properties of Fel vary in different cell types. While Gal4-Fel constructs strongly activated transcription in Cos-7 cells and the MCF-7 breast tumor cell line, they displayed low to no activity in the precursor B-cell line REH, breast tumor cell line Gl-101A and epithelial-derived A431 cells. These data are consistent with a potential role of Hrx-Fel as a chimeric transcription factor in which Fel contributes transcriptional effector properties and suggest the requirement for cell-specific accessory factors.
Morrissey
J J
JJ
Motorola, Biological Research Program, Ft. Lauderdale, FL 33322, USA.
Raney
S
S
Cleary
M L
ML
D000256:Adenoviridae / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011392:Proline / Q000032:analysis; D011519:Proto-Oncogenes; D015183:Restriction Mapping; D012694:Serine / Q000032:analysis; D014157:Transcription Factors; D015533:Transcriptional Activation; D035602:Transcriptional Elongation Factors; D014162:Transfection; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D017501:Adenovirus E1B Proteins; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D012694:Serine; D011392:Proline; D011495:Histone-Lysine N-Methyltransferase