The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications

A Runt domain transcription factor AML1/RUNX1 is essential for generation and differentiation of definitive hematopoietic stem cells. AML1 is the most frequent target of chromosomal translocations in acute leukemias. Several chimeric proteins such as AML1-MTG8 and TEL-AML1 have transdominant propert...

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Bibliographic Details
Published in:Critical reviews in oncology/hematology 2003-02, Vol.45 (2), p.129-150
Main Author: Asou, Norio
Format: Article
Language:English
Subjects:
Acute myeloblastic leukemia
Adult
Aged
Aged, 80 and over
AML1
Biological and medical sciences
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Familial platelet disorder
Haploinsufficiency
Hematologic and hematopoietic diseases
Histone deacetylation
Humans
Leukemia, Myeloid - genetics
Leukemia, Myeloid - physiopathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Middle Aged
Molecular target therapy
PEBP2β
Point Mutation
Proto-Oncogene Proteins
RUNX1
Transcription Factors - genetics
Transcription Factors - physiology
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Summary:A Runt domain transcription factor AML1/RUNX1 is essential for generation and differentiation of definitive hematopoietic stem cells. AML1 is the most frequent target of chromosomal translocations in acute leukemias. Several chimeric proteins such as AML1-MTG8 and TEL-AML1 have transdominant properties for wild-type AML1 and acts as transcriptional repressors. The transcriptional repression in AML1 fusion proteins is mediated by recruitment of nuclear corepressor complex that maintains local histone deacetylation. Inhibition of the expression of AML1-responsive genes leads to a block in hematopoietic cell differentiation and consequent leukemic transformation. On the other hand, mutations in the Runt domain of the AML1 are identified in both sporadic acute myeloblastic leukemia (AML) without AML1 translocation and familial platelet disorder with predisposition to AML. These observations indicate that a decrease in AML1 dosage resulting from chromosomal translocations or mutations contributes to leukemogenesis. Furthermore, dysregulated chromatin remodeling and transcriptional control appears to be a common pathway in AML1-associated leukemias that could be an important target for the development of new therapeutic agents.
ISSN:1040-8428
1879-0461
DOI:10.1016/S1040-8428(02)00003-3