MYND-less splice variants ofAML1-MTG8 (RUNX1-CBFA2T1) are expressed in leukemia with t(8;21)
| Autor: | Tomoko Kozu, Tomofusa Fukuyama, Kiwamu Akagi, Yasuhiko Kaneko, Tohru Yamami |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Cancer Research Chromosomes Human Pair 21 Molecular Sequence Data Biology Translocation Genetic Fusion gene chemistry.chemical_compound RUNX1 Translocation Partner 1 Protein Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Genetics Humans Sequence Deletion Leukemia ABL Base Sequence Alternative splicing RUNX1T1 Genetic Variation Myeloid leukemia Molecular biology Fusion protein DNA-Binding Proteins Alternative Splicing RUNX1 chemistry Core Binding Factor Alpha 2 Subunit Female Corepressor Gene Deletion Chromosomes Human Pair 8 Transcription Factors |
| Zdroj: | Genes, Chromosomes and Cancer. 43:45-53 |
| ISSN: | 1098-2264 1045-2257 |
| DOI: | 10.1002/gcc.20165 |
| Popis: | The AML1–MTG8 fusion gene is generated by chromosome translocation t(8;21), which is frequently observed in acute myeloid leukemia. The fusion gene produces a chimeric transcription factor that suppresses the expression of AML1-target genes via the MTG8 part of the chimeric protein, which is thought to be the primary cause of leukemia. The C-terminal region of MTG8 contains the MYND domain, represented by highly conserved zinc-finger-like protein motifs, and is known to interact with corepressor proteins. We found that, instead of the MYND domain, an alternative last exon of MTG8 encoding 27 amino acids in-frame is expressed naturally in human adult testis and in several leukemia cell lines. This type of alternative splicing also occurred in the AML1–MTG8 fusion gene at high levels in leukemia cell lines with t(8;21), as well as in blast cells of leukemia patients with t(8;21). The variant proteins of both MTG8 and AML1–MTG8 reduced transcriptional repressor activity in a mammalian two-hybrid assay. However, mixed expression of these variants with wild-type MTG8 recovered their repressor activity, suggesting that these variants also act as repressors in vivo where wild-type MTG8 and other family members exist in abundance. On the other hand, the MYND-less variants acquired a higher affinity for binding to MTG8 and formed a multimer, whereas the wild-type protein forms a dimer. Thus, expression of the MYND-less variants by the dysregulation of splicing machinery, which stimulates the oligomerization of fusion proteins in leukemia cells, may enhance malignant conversion of hematopoietic cells. © 2005 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text