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  • Original Paper
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Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia

Oncogene volume 20, pages 8236–8248 (2001)Cite this article

Abstract

The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.

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Acknowledgements

We are grateful to Jennifer Joyce for technical assistance and to Mike Jennings and Glenn Paradis for assistance and advice in flow cytometry cell sorting. GM Cuenco is supported by the National Institutes of Health Training Grant GM07122. R Ren is a recipient of the Leukemia Society of America Scholar Award.

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  1. Department of Biology, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454, Massachusetts, USA

    Grace M Cuenco & Ruibao Ren

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  1. Grace M Cuenco
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Correspondence to Ruibao Ren.

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Cuenco, G., Ren, R. Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Oncogene 20, 8236–8248 (2001). https://doi.org/10.1038/sj.onc.1205095

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