Acute Myeloid Leukemia Research Today is a free monthly online journal that collates and summarizes the latest research about Acute Myeloid Leukemia, including details on aml, symptoms, treatment, information. | ||||||||
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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.Senyuk V, Li D, Zakharov A, Mikhail FM, Nucifora G Department of Pathology and The Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60607, USA. vsenyuk@uic.edu 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. Published 5 September 2005 in Cancer Res, 65(17): 7603-11.
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