The distal zinc finger domain of AML1/MDS1/EVI1 is an oligomerization domain involved in induction of hematopoietic differentiation defects in primary cells in vitro.
AML1/MDS1/EVI1 (AME) is a chimeric transcription factor produced by the (3;21)(q26;q22) translocation. This chromosomal translocation is associated with de novo and therapy-related acute myeloid leukemia and with the blast crisis of chronic myelogenous leukemia. AME is obtained by in-frame fusion of the AML1 and MDS1/EVI1 (ME) genes. The mechanisms by which AME induces a neoplastic transformation in bone marrow cells are unknown. AME interacts with the corepressors CtBP and HDAC1, and it was shown that AME is a repressor in contrast to the parent transcription factors AML1 and ME, which are transcription activators. Studies with murine bone marrow progenitors indicated that the introduction of a point mutation that destroys the CtBP-binding consensus impairs but does not abolish the disruption of cell differentiation and replication associated with AME expression, suggesting that additional events are required. Several chimeric proteins, such as AML1/ETO, BCR/ABL, and PML/RARa, are characterized by the presence of a self-interaction domain critical for transformation. We report that AME is also able to oligomerize and displays a complex pattern of self-interaction that involves at least three oligomerization regions, one of which is the distal zinc finger domain. Although the deletion of this short domain does not preclude the self-interaction of AME, it significantly reduces the differentiation defects caused in vitro by AME in primary murine bone marrow progenitors. The addition of a point mutation that inhibits CtBP binding completely abrogates the effects of AME on differentiation, suggesting that AME induces hematopoietic differentiation defects through at least two separate but cooperating pathways.
Senyuk
Vitalyi
V
Department of Pathology and The Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60607, USA. vsenyuk@uic.edu
Li
Donglan
D
Zakharov
Alexander
A
Mikhail
Fady M
FM
Nucifora
Giuseppina
G
D000429:Alcohol Oxidoreductases; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology*
C460199:AML1-MDS1-EVI1 fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D012097:Repressor Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein