MYND-less splice variants of AML1-MTG8 (RUNX1-CBFA2T1) are expressed in leukemia with t(8;21).
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.
Kozu
Tomoko
T
Research Institute for Clinical Oncology, Saitama Cancer Center, Ina, Saitama, Japan. kozu@cancer-c.pref.saitama.jp
Fukuyama
Tomofusa
T
Yamami
Tohru
T
Akagi
Kiwamu
K
Kaneko
Yasuhiko
Y
D017398:Alternative Splicing; D001483:Base Sequence; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors