AML1-FOG2 fusion protein in myelodysplasia.
Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of acute myeloid leukemia 1 (AML1)/RUNX1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 in-frame to the novel partner gene FOG2/ZFPM2. The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses the transcriptional activity of both CBF and GATA1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and these proteins associate in a protein complex. These results suggest a central role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATAdevelopmental programs in the pathogenesis of myelodysplasia.
Chan
Edward M
EM
Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, 1044 W Walnut St, R4-202, Indianapolis, IN 46202-5254, USA. echan@iupui.edu
Comer
Elisha M
EM
Brown
Frank C
FC
Richkind
Kathleen E
KE
Holmes
Melissa L
ML
Chong
Beng H
BH
Shiffman
Roger
R
Zhang
Dong-Er
DE
Slovak
Marilyn L
ML
Willman
Cheryl L
CL
Noguchi
Constance T
CT
Li
Yanjun
Y
Heiber
Devan J
DJ
Kwan
Lori
L
Chan
Rebecca J
RJ
Vance
Gail H
GH
Ramsey
Heather C
HC
Hromas
Robert A
RA
D000429:Alcohol Oxidoreductases; D023081:CCAAT-Binding Factor / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D041321:Chromosomes, Human, X; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic
C501878:AML1-FOG2 fusion protein, human; D023081:CCAAT-Binding Factor; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein