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 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. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.