ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein.
The multiplicity of transcription factors involved in hematologic malignancies suggests a complicated scenario in which many different molecular mechanisms lead to malignant transformation. We hypothesized that some of these proteins might physically and functionally interact and thus mechanistically link different diseases. The ETO protein of t(8;21) acute myeloid leukemia (AML) is an excellent candidate as a common factor because it is normally expressed in human hematopoietic cells, it binds to histone deacetylases (HDACs), and it interacts with the PLZF protein of t(11;17) acute promyelocytic leukemia. To determine whether ETO functionally links a broader range of disease entities, we asked whether ETO forms a complex with the Bcl-6 oncoprotein of B-cell lymphomas. We found that ETO and Bcl-6 are coexpressed in normal and malignant lymphoid tissue, where they interact and colocalize in nuclear speckles. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression of artificial and endogenous genes in an HDAC-dependent manner, and forms a complex with Bcl-6 on the promoters of its endogenous target genes in B-cell lymphoma cells. Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies.
Chevallier
Nathalie
N
Department of Medicine, Mount Sinai School of Medicine, One Gustave Levy Pl, New York, NY 10029, USA.
Corcoran
Connie M
CM
Lennon
Christine
C
Hyjek
Elizabeth
E
Chadburn
Amy
A
Bardwell
Vivian J
VJ
Licht
Jonathan D
JD
Melnick
Ari
A
D000208:Acute Disease; D001402:B-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D007951:Leukemia, Myeloid / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014178:Translocation, Genetic; D016335:Zinc Fingers / Q000502:physiology
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D014157:Transcription Factors