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 pathogene...

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Bibliographic Details
Published in:Blood 2005-06, Vol.105 (11), p.4523-4526
Main Authors: Chan, Edward M., Comer, Elisha M., Brown, Frank C., Richkind, Kathleen E., Holmes, Melissa L., Chong, Beng H., Shiffman, Roger, Zhang, Dong-Er, Slovak, Marilyn L., Willman, Cheryl L., Noguchi, Constance T., Li, Yanjun, Heiber, Devan J., Kwan, Lori, Chan, Rebecca J., Vance, Gail H., Ramsey, Heather C., Hromas, Robert A.
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases
Biological and medical sciences
CCAAT-Binding Factor - genetics
Chromosomes, Human, Pair 21
Chromosomes, Human, X
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Erythroid-Specific DNA-Binding Factors
GATA1 Transcription Factor
Hematologic and hematopoietic diseases
Humans
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Myelodysplastic Syndromes - etiology
Myelodysplastic Syndromes - genetics
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Phosphoproteins - metabolism
Protein Binding
Repressor Proteins
Transcription Factors - genetics
Transcription, Genetic
Translocation, Genetic
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2004-07-2762