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Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal

Tonks, Alex, Tonks, Amanda Jayne, Pearn, Lorna, Pearce, L., Hoy, T., Couzens, Stephen, Fisher, J., Burnett, Alan Kenneth and Darley, Richard Lawrence 2004. Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal. Leukemia 18 (7) , pp. 1238-1245. 10.1038/sj.leu.2403396

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The t(8;21) translocation is one of the most frequent translocations in acute myeloid leukaemia (AML), giving rise to the AML1-ETO fusion protein (or RUNX1-CBF2T1). This abnormality is associated with myelocytic leukaemia with dysplastic granulopoiesis. Here, we demonstrate that when expressed in a normal human (CD34(+)) progenitor population, AML1-ETO selectively inhibits granulocyte colony formation but not monocyte colony formation. In bulk liquid culture, we found that though AML1-ETO transiently inhibited the proliferation of CD34(+) cells, it promoted long-term growth of myeloid cells for more than 80 days, suggesting that differentiation was inhibited. In support of this, cultures expressing AML1-ETO demonstrated enhanced retention of colony-forming capacity. Phenotypic examination of AML1-ETO cultures revealed a defect in granulocytic differentiation in terms of retention of CD34(+) cells within the culture and delayed CD11b upregulation. Morphologically, granulocyte terminal differentiation in AML1-ETO-expressing cells was inhibited by 83+/-5%, giving rise to a build-up of early to intermediate granulocytes that exhibited a number of morphological features associated with t(8;21) leukaemias. In contrast, AML1-ETO had little or no effect on monocytic differentiation. Taken together, these results suggest that expression of AML1-ETO selectively inhibits the differentiation of granulocytic cells and promoted extensive self-renewal, supporting a causal role for t(8;21) translocations in leukaemogenesis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: Antigens CD34, Cell Culture Techniques / methods, Cell Differentiation, Cell Division, Core Binding Factor Alpha 2 Subunit,Erythroid Cells / pathology,Granulocyte Precursor Cells / pathology*, Green Fluorescent Proteins, Humans, Immunophenotyping, Leukemia Myelomonocytic Acute / etiology, Leukemia Myelomonocytic Acute / pathology*, Luminescent Proteins / genetics, Myeloid Cells / pathology, Oncogene Proteins Fusion / genetics, Oncogene Proteins Fusion / physiology*, Time Factors, Transcription Factors/ genetics, Transcription Factors / physiology*, Transduction, Genetic Substances AML1-ETO fusion protein, human Antigens, CD34 Core Binding Factor Alpha 2 Subunit Luminescent Proteins Oncogene Proteins, Fusion Transcription Factors Green Fluorescent Proteins
Additional Information: Publication Types Research Support, Non-U.S. Gov't Full Text Sources Nature Publishing Group EBSCO Ovid Technologies, Inc. ProQuest Other Literature Sources COS Scholar Universe Labome Researcher Resource - ExactAntigen/Labome
Publisher: Nature Publishing Group
ISSN: 0887-6924
Last Modified: 14 Dec 2020 02:43

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